1,4-dihydropyridine derivatives

ABSTRACT

1,4-dihydropyridine derivatives and optically active 1,4-dihydropyridine derivatives with the following formula, having vasodilating activity based on calcium antagonism, and PAF antaognism, and methods of producing the same are disclosed: ##STR1## wherein (*) indicates a chiral center in the case of the optically active 1,4-dihydropyridine derivatives.

BACKGROUND OF THE INVENTION

The present invention relates to 1,4-dihydropyridine derivatives andoptically active 1,4-dihydropyridine derivatives having (a) vasodilatingactivity based on calcium antagonism and (b) PAF antagonism, and methodsof producing the optically active 1,4-dihydropyridine derivatives.

Generally it is known that 1,4-dihydropyridine derivatives are useful asremedies for diseases of circulatory system such as remedies forischemic heart disease, cerebral circulatory disease and hypertension,since the 1,4-dihydropyridine derivatives have vasodilating activitybased on the calcium antagonism thereof.

It has been reported that it is essential that the 1,4-dihydropyridinederivatives have a 3,5-diester structure in order that the1,4-dihydropyridine derivatives exhibit the above-mentioned actions.

Representative examples of such 1,4-dihydropyridine derivatives are1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylicacid dimethyl ester (Generic name: "NIFEDIPINE" as described in U.S.Pat. No. 3,644,627) and1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylicacid-3-[2-(N-benzyl-N-methylamino)ethyl]ester-5-methyl esterhydrochloride (Generic name: "NICARDIPINE" as described in JapanesePatent Publication 55-45075).

Furthermore, as the conventional methods of producing optically active1,4-dihydropyridine-3-carboxylate derivatives, there are known, forinstance, (a) a method comprising the steps of subjecting1,4-dihydropyridine-3-carboxylic acid derivatives to optical resolutionto obtain optically active 1,4-dihydropyridine-3-carboxylic acidderivatives, (refer to T. Shibanuma et al., Chem. Pharm. Bull. 28, 2809(1980)) to 1,4-dihydropyridine-3,5dicarboxylate derivatives and (b) amethod of subjecting diastereomers of1,4-dihydropyridine-3,5-dicarboxylate derivatives to optical resolution(refer to Japanese Laid-Open Patent Application 56-36455).

Platelet-activating factor (PAF) is produced by many types ofpre-phlogocytes, platelet and liver, liberated, and exhibits not onlystrong platelet aggregation activity, but also biological activities ina wide range, which are induced directly or through the liberation ofother strong mediators such as thromboxane A₂ and leucotriene. Thereforeit is considered that compounds having PAF antagonism are useful forremedies for varieties of allergic diseases, inflammatory diseases, andhyperexcretory diseases, such as asthma, arthritis, and bronchitis.Furthermore, recent studies have revealed that PAF is capable ofinducing the reduction of the blood flow volume of coronary artery.Therefore it is also considered that PAF antagonists will be useful asremedies for angina pectoris.

As PAF antagonists, varieties of compounds such as PAF analogues andbenzodiazepine derivatives has been reported.

However, a compound having (a) vasodilating activity based on calciumantagonism and (b) PAF antagonism have not yet been discovered.

SUMMARY OF THE INVENTION

It is therefore a first object of the present invention to provide1,4-dihydropyridine derivatives having vasodilating activity based oncalcium antagonism, and PAF antagonism.

A second object of the present invention is to provide optically active1,4-dihydropyridine derivatives having vasodilating activity based oncalcium antagonism, and PAF antagonism.

A third object of the present invention is to provide methods ofproducing the above 1,4-dihydropyridine derivatives and optically active1,4-dihydropyridine derivatives.

The present invention is based on the discovery that 1,4-dihydropyridinederivatives in which various amino acid derivatives are amido-bonded toeither the position 3 or position 5 or both positions of the1,4-dihydropyridine ring exhibit antihypertensive action or PAFantagonism the same as or greater than that exhibited by theconventional 1,4-dihydropyridine-3,5-diester derivatives.

The first object of the present invention is achieved by1,4-dihydropyridine derivatives of formula (I): ##STR2## wherein R¹represents hydrogen, a straight chain, branched chain or cyclic alkylgroup, an unsubstituted or substituted aromatic hydrocarbon group, or anunsubstituted or substituted aromatic heterocyclic group; R² representshydrogen, a straight chain, branched chain or cyclic alkyl group, and R¹and R² in combination may form a saturated or unsaturated hydrocarbonring; R⁴ and R⁵ each represent hydrogen, an unsubstituted or substitutedstraight chain, branched chain or cyclic alkyl group, an unsubstitutedor substituted amino group, an unsubstituted or substituted aromatichydrocarbon group, or an unsubstituted or substituted aromaticheterocyclic group; R⁶ represents hydrogen, a straight chain, branchedchain or cyclic alkyl group, or a trialkylsilyl group; B represents anunsubstituted or substituted alkylene group, an unsubstituted orsubstituted aromatic hydrocarbon group, an unsubstituted or substitutedaromatic heterocyclic group, an unsubstituted or substitutedcycloalkylydene group; R⁷ represents an unsubstituted or substitutedstraight chain, branched chain or cyclic alkoxyl group, an unsubstitutedor substituted amino group, or an unsubstituted or substituted cyclicamino group; R³ represents hydrogen, cyano group, nitro group, --COR⁸,an unsubstituted or substituted aromatic hydrocarbon group, or anunsubstituted or substituted aromatic heterocyclic group, in which R⁸represents an unsubstituted or substituted straight chain, branchedchain or cyclic alkoxyl group, an alkenyloxy group, an alkynyloxy group,or --N(R⁶¹)--B¹ --COR⁷¹, in which R⁶¹, R⁷¹ and B¹ are respectively thesame as R⁶, R⁷, and B.

The second object of the present invention is achieved by opticallyactive 1,4-dihydropyridine derivatives of formula (I-a): ##STR3##wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B are respectively the same asin formula (I), and * indicates a chiral center.

The third object of the present invention with respect to the productionof 1,4-dihydropyridine derivatives of formula (I) is achieved by any ofthe following three processes:

[Process 1]

A ketone compound of formula (II) is allowed to react with an acrylamidecompound of formula (III) in the following reaction scheme: ##STR4##wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B are respectively the same asin formula (I).

[Process 2]

An amide compound of formula (IV) is allowed to react with an aminocompound of formula (V) in the following reaction scheme: ##STR5##wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B are respectively the same asin formula (I).

[Process 3]

A carboxylic acid derivative of formula (VI) is allowed to react with anamine compound of formula (VII) in the following reaction scheme:##STR6## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B are respectively thesame as in formula (I), and Z represents a hydroxyl group, a halogenatom, or an active ester residue.

In the third object of the present invention, the optically active1,4-dihydropyridine derivatives of formula (I-a) are produced by any ofthe following three processes:

[Process 4]

A keto-ester derivative of formula (X) is allowed to react with anoptically active enamine derivative of formula (XI) in the followingreaction scheme: ##STR7## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B arerespectively the same as in formula (I), R¹⁷ and R¹⁸ are different andindependently represent an unsubstituted or substituted straight chain,branched chain or cyclic alkyl group, an unsubstituted or substitutedaromatic hydrocarbon group, an unsubstituted or substituted aralkylgroup, an unsubstituted or substituted straight chain, branched chain orcyclic alkoxycarbonyl group, or an unsubstituted or substituted straightchain, branched chain or cyclic aminocarbonyl group, and * indicates achiral center.

[Process 5]

An N-acylamino acid derivative of formula (XIV) is allowed to react withan optically active enamine derivative of formula (XV) in the followingreaction scheme, followed by allowing the product to react with ammoniaor an ammonium salt: ##STR8## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁷,R¹⁸, and B are respectively the same as previously defined, and *indicates a chiral center.

[Process 6]

A ketone derivative of formula (XVI) is allowed to react with anoptically active acrylamide derivative of formula (XVII) in thefollowing reaction scheme, followed by allowing the product to reactwith ammonia or an ammonium salt: ##STR9## wherein R¹, R², R³, R⁴, R ⁵,R⁶, R⁷, R¹⁷, R¹⁸, and B are respectively the same as previously defined,and * indicates a chiral center.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the 1,4-dihydropyridine derivatives of formula (I) and the opticallyactive 1,4-dihydropyridine derivatives of formula (I-a), R¹ representshydrogen, a straight chain, branched chain or cyclic alkyl group having1 to 6 carbon atoms, such as methyl group, ethyl group, propyl group,butyl group, pentyl group, hexyl group, 2-propyl group, t-butyl group,cyclopentyl group, and cyclohexyl group; an aromatic hydrocarbon groupor an aromatic heterocyclic group such as phenyl group, pyridyl group,quinolyl group, isoquinolyl group, furyl group, thienyl group,benzoxazolyl group, benzthiazolyl group, pyridazinyl group, pyrazinylgroup, pyrimidyl group, indolyl group, naphthyl group, benzoxadiazolylgroup, and benzthiadiazolyl group, which may have a substituent selectedfrom the group consisting of a halogen atom such as fluorine, chlorine,bromine or iodine; hydroxyl group; cyano group; nitro group;trifluoromethyl group, trichloromethyl group, azide group; amino group;a lower alkyl group having 1 to 6 carbon atoms, such as methyl group,ethyl group, propyl group, butyl group, pentyl group or hexyl group; alower alkoxyl group having such as methoxy group, ethoxy group, propoxygroup, butoxy group, pentyloxy group, or hexyloxy group; benzoyl group;a lower alkylthio group such as methythio group, ethylthio group,propylthio group, butylthio group, pentylthio group, or hexylthio group;phenylthio group; phenoxy group; a lower alkoxycarbonyl group such asmethoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group,butoxycarbonyl group, or pentyloxycarbonyl group; a lower acyl groupsuch as acetyl group, propyonyl group, butylyl group, pentanoyl group,or hexanoyl group; benzyloxy group; and cinnamyloxy group.

R² represents hydrogen, the same straight chain, branched chain orcyclic alkyl group as represented by R¹. R² may be combined with R¹ toform a saturated or unsaturated hydrocarbon ring. Examples of such ahydrocarbon ring include cyclopentane ring, cyclohexane ring, andtetrahydronaphthalene ring.

R⁴ and R⁵ each represent hydrogen, the same straight chain, branchedchain or cyclic alkyl group as represented by R¹ a substituted straightchain branched chain or cyclic alkyl group such as trifluoromethylgroup, or trichloromethyl group, an unsubstituted or substituted aminogroup such as amino group, dimethylamino group, diethylamino group, ordipropylamino group, or the same aromatic hydrocarbon group or aromaticheterocyclic group as represented by R¹.

R⁶ represents hydrogen, the same straight chain, branched chain orcyclic alkyl group as represented by R¹, or a trialkylsilyl group.

B represents an unsubstituted or substituted alkylene group, anunsubstituted or substituted aromatic hydrocarbon group, anunsubstituted or substituted aromatic heterocyclic group or anunsubstituted or substituted cycloalkylydene group. Examples of thesegroups include methylene group, ethylene group, ethylydene group,isopropylydene group, 2-phenylethylydene group, 3-methylbutylydenegroup, 3-(t-butoxycarbonyl)propylydene group, phenylenediyl group,phenylenediyl group, cyclohexylydene group, and pyrazinediyl group.

R⁷ represents an unsubstituted or substituted straight chain, branchedchain or cyclic alkoxyl group, an unsubstituted or substituted aminogroup, or an unsubstituted or substituted cyclic amino group.

Examples of the unsubstituted or substituted alkoxyl group as follows:methoxy group, ethoxy group, n-propyloxy group, n-butoxy group,n-pentyloxy group, n-hexyloxy group, n-heptyloxy group, n-octyloxygroup, n-nonyloxy group, n-decyloxy group, isopropyloxy group,isobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, aryloxygroup, 2-propyn-1-yloxy group, (E)-2-buten-1-yloxy group,(E)-3-buten-1-yloxy group, (E)-2-penten-1-yloxy group,(2E,4E)-2,4-hexadienyloxy group, 2,4-hexadiynyloxy group,(E)-hexa-4-ene-2-yloxy group, (E)-3-phenyl-2-propen-1-yloxy group,(Z)-3-phenyl-2-propen-1-yloxy group, 3-phenyl-2-propyn-1-yloxy group,(2E,4E)-5-phenyl-2,4-pentadien-1-yloxy group,5-phenyl-penta-2,4-diyn-1-yloxy group, (E)-5phenyl-penta-2-ene-4-yn-1-yloxy group, (E)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yloxy group,(E)-3-[3-1imidazolylmethyl)phenyl]-2-propen-1yloxy group,(E)-3-[2-(1-imidazolylmethyl)phenyl]-2-propen-1-yloxy group,(E)-3-[4-(1-imidazolyl)phenyl]-2-propen-1-yloxy group,(Z)-3-[4-(1-imidazolylmethyl)phenyl]-2-propen-1-yloxy group, (E)-3-[6-(1-imidazolylmethyl)pyridin-2-yl]-2-propen-1-yloxy group,(E)-3-[5-(1-imidazolylmethyl)furan-2-yl]-2-propen-1-yloxy group,(E)-3-[5-(1-imidazolylmethyl)thiophen-2-yl]-2-propen-1-yloxy group,(E)-3-phenyl-1-methyl-2-propen-1yloxy group,(E)-1-fluoro-3-phenyl-2-propen-1-yloxy group, 2-methoxyethyloxy group,3-methoxypropyloxy group, 3-ethoxypropyloxy group, 2-phenoxyethyloxygroup, 2-phenylthioethyloxy group, 2-(N-methylamino)ethyloxy group,2-(N,N-dimethyl-amino)ethyloxy group, 2-(N-methyl-N-phenylamino)ethyloxygroup, 2-(N,N-diethyl)aminoethyloxy group,2-(N-benzyl-N-methyl)aminoethyloxy group 2-(1-piperazinyl)ethyloxygroup, 4-(1-piperazinyl)butyloxy group, 6-(1-piperazinyl)hexyloxy group,2-(4-piperidinyl)ethyloxy group, 2-(4-phenylpiperazin-1-yl)ethyloxygroup, 3-(4-phenylpiperazin-1-yl)-propyloxy group,4-(4-phenylpiperazin-1-yl)butyloxy group,6-(4-phenylpiperazin-1-yl)hexyloxy group,2-(4-phenylpiperidin-1-yl)ethyloxy group,3-(4-phenylpiperidin-1-yl)-propyloxy group,4-(4-phenylpiperidin-1-yl)butyloxy group,6-(4-phenylpiperidin-1-yl)hexyloxy group,2-[4-(diphenylmethyl)piperazin-1-yl]ethyloxy group,3-[4-(diphenylmethyl)piperazin-1-yl]propyloxy group,4-[4-(diphenylmethyl)piperazin-1-yl]butyloxy group,6-[4-(diphenylmethyl)piperazin-1-yl]hexyloxy group 2-morpholinoethyloxygroup, N-benzylpyrrolidin-3-yloxy group, N-benzylpiperidin-3-yloxygroup, 2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethyloxy group,2,2,2-trifluoroethyloxy group,2-(3,7-dihydro-3,7-dimethyl-1H-purine-2,6-dion-1-yl)ethyloxy group, and2-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purin-7-yl)ethyloxy.

Examples of the unsubstituted or substituted amino group or cyclic aminogroup are as follows: dimethylamino group, diethylamino group,dipropylamino group, diisopropylamino group, piperidinyl group,piperazinyl group, morpholino group, pyrrolidinyl group,4-phenylpiperidinyl group, 4-phenylpiperazinyl group,4-diphenylmethylpiperazinyl group, methoxycarbonylmethylamino group,ethoxycarbonylmethylamino group, isopropyloxycarbonylmethylamino group,t-butoxycarbonylmethylamino group,1-(t-butoxycarbonyl)-2-methylpropylamino group,1-(t-butoxycarbonyl)ethylamino group,1-(t-butoxycarbonyl)-2-phenylethylamino group,1-(2-methoxyethoxycarbonyl)-2-methylpropylamino group,1-(ethoxycarbonyl)-1-methylethylamino group,2-(ethoxycarbonyl)ethylamino group, andN-methyl-N-ethoxycarbonylmethylamino group.

R³ represents hydrogen, cyano group, nitro group, --COR⁸, the sameunsubstituted or substituted aromatic hydrocarbon group, or the sameunsubstituted or substituted aromatic heterocyclic group as representedby R¹. R⁸ represents an unsubstituted or substituted straight chain,branched chain or cyclic alkoxyl group, an alkenyloxy group, analkynyloxy group, or --N(R⁶¹)--B¹ --COR⁷¹, in which R⁶¹, R⁷¹ and B¹ arerespectively the same as R⁶, R⁷, and B which are defined previously.Examples of the above-mentioned unsubstituted or substituted straightchain, branched chain or cyclic alkoxyl group are those of the alkoxylgroup defined by R⁷.

Specific examples of the 1,4-dihydropyridine derivatives represented bythe previously mentioned formula (I) are as follows:

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl[-3-methylbutylate,

(+)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

(+)-t-butyl 2-(S)-[N-[1,4 -dihydro-2,6 -dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

(-)-t-butyl2-(R)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

(-)-t-butyl 2-(R)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

(+)-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

(-)-t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate,

t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]pyrrolidine-2-carboxylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(2-chlorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(2-chlorophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(2-chlorophenyl)pyridine-3-carbonyl]amino]propionate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4(2-chlorophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate,

t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]pyrrolidine-2-carboxylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]-4-methylpentanoate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]-3-(1-t-butoxycarbonyl)butylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-fluorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-trifluoromethylphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methylphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,4,6-trimethoxyphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-fluorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-trifluoromethylphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-cyanophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methoxyphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-hydroxyphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-cyclohexylpyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-cyanophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-cyanophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-methylphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-t-butoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxy-carbonyl-4-(3-nitrophenyl)pyridine-3 -carbonyl]amino]-3-methylbutylate,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoyl]pyrrolidine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoyl]-4-phenylpiperidine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoyl]-4-diphenylmethylpiperidine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3nitrophenyl)pyridine-3-carbonyl]amino]acetyl]pyrrolidine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3nitrophenyl)pyridine-3-carbonyl]amino]acetyl]-4-phenylpiperazine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetyl]-4-diphenylmethylpiperazine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoyl]-4-(2-pyridyl)piperazine,

1-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoyl]-4-(2-pyrimidyl)piperazine,

t-butyl2-[N-[5-[N-(t-butoxycarbonyl)methylcarbamoyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

isopropyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl-N-methylamino]acetate,

ethyl1-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]cyclohexanecarboxylate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]benzoate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]isobutyrate,

ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]pyrazine-2-carboxylate,

t-butyl2-[N-[1,4-dihydro-6-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-6-phenylpyridine-3-carbonyl]amino]acetate,

2-methoxyethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3carbonyl]amino]-3-methylbutylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methylphenyl)pyridine-3-carbonyl]amino]acetate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-methylpentanoate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-2-cyclopropanecarboxylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-2-cyclopentanecarboxylate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]nicotinate,

ethyl6-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]nicotinate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-2-thiopheneacetate,

ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-1,2,4-triazole-5-carboxylate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-2-phenylacetate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]butyrate,

ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]butyrate,

ethyl4-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]butyrate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]hexanoate,

ethyl6-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]hexanoate,

ethyl7-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]heptanoate,

ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate,

ethyl4-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-2-chlorobenzoate,

ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-chlorobenzoate,

ethyl2-[1-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]piperidinecarboxylate,

ethyl2-[1-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]pyrrolecarboxylate,

t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-hydroxypropionate

t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-4,6-dimethyl-2-phenylpyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(2-ethyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-6-methyl-2-(2-methoxy-4-methylthiophenyl)-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate,

(+)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3carbonyl)amino]propionate,

(-)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl)amino]propionate,

(+)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl)amino]-3phenylpropionate,

(-)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl)amino]-3-phenylpropionate,

(+)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3carbonyl)amino]-4-methylpentanoate,

(-)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3carbonyl)amino]-4-methylpentanoate,

(+)-t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3carbonyl)amino]-4-(t-butoxycarbonyl)butylate,

(-)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-(t-butoxycarbonyl)butylate,

(+)-t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]pyrrolidine-2-(S)-carboxylate,

(-)-t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]pyrrolidine-2-(S)-carboxylate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-fluorophenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,4,6-trimethoxyphenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methoxyphenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-trifluoromethylphenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(4-cyclohexyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-2,4,6-trimethylpyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-nitrophenyl)pyridine-3-carbonyl)amino]acetate,

t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carbonyl)amino]acetate,

t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-nitrophenyl)pyridine-3-carbonyl)amino]-3-methylbutylate,

t-butyl2-(S)-[N-(4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carbonyl)amino]-3-methylbutylate,

t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-trifluoromethylphenyl)pyridine-3-carbonyl)-amino]-3-methylbutylate,

t-butyl2-(S)-[N-(4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carbonyl)amino]-3-methylbutylate,

t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methylphenyl)pyridine-3-carbonyl)amino]-3-methylbutylate,

t-butyl2-(S)-[N-(1,4-dihydro-5-methoxycarbonyl-2,4,6-trimethylpyridine-3-carbonyl)amino]-3-methylbutylate,and

t-butyl2-(S)-[N-(1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridine-3-carbonyl)amino]-3-methylbutylate.

The 1,4-dihydropyridine derivatives of the previously mentioned formula(I) can be produced by any of the following three processes:

[Process 1]

A ketone compound of formula (II) is allowed to react with an acrylamidecompound of formula (III) in the following reaction scheme: ##STR10##wherein R¹, R² R³, R⁴, R⁵, R⁶, R⁷, and B are respectively the same as informula (I).

The above reaction can be carried out by mixing the ketone compound offormula (II) and the acrylamide compound of formula (III) in an inertsolvent or without any solvent at 0° C. to 150° C., preferably at 80° C.to 120° C.

Examples of the inert solvent for use in the above reaction includearomatic hydrocarbons such as benzene, toluene and xylene; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane, andchloroform; alcohols such as methanol, and ethanol; ethers such asdiethyl ether, tetrahydrofuran, and dioxane; dimethylformamide; anddimethyl sulfoxide.

It is also preferable that the above reaction be carried out in anatmosphere of an inert gas such as nitrogen gas or argon gas, and in thedark.

Furthermore, in order to carry out the above reaction efficiently, it ispreferable that an equivalent amount of the ketone compound of formula(II) be employed with respect to the acrylamide compound of formula(III). [Process 2]

An amide compound of formula (IV) is allowed to react with an aminocompound of formula (V) in the following reaction scheme under the sameconditions as in Process 1: ##STR11## wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, and B are respectively the same as in formula (I).

[Process 3]

A carboxylic acid derivative of formula (VI) is allowed to react with anamine compound of formula (VII) in the following reaction scheme:##STR12## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B are respectively thesame as in formula (I), and Z represents a hydroxyl group, a halogenatom, or an active ester residue.

In the carboxylic acid derivative of formula (VI), when Z is a hydroxylgroup, the reaction can be carried out in the presence of a condensationagent. Examples of the condensation agent include carbodiimide agentssuch as N,N-dicyclohexylcarbodiimide and1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride.

The above reaction can be carried in an inert solvent at 0° C. to 150°C., preferably at 20° C. to 120° C.

Examples of the inert solvent for use in the above reaction includehalogenated hydrocarbons such as dichloromethane, chloroform, and1,2-dichloroethane; hydrocarbons such as benzene, toluene and xylene;ethers such as ether, tetrahydrofuran, and dioxane; dimethylformamide;and dimethyl sulfoxide.

It is also preferable that the above reaction be carried out in anatmosphere of an inert gas such as nitrogen gas or argon gas, and in thedark.

In the above reaction, the carbodiimide agents can be employed in anamount of 1 to 1.5 equivalents with respect to the carboxylic acidderivative of formula (VI) and the amine compound of formula (VII).

When Z in formula (VI) is a hydroxyl group, the carboxyl group in thecarboxylic acid derivative of formula (VI) is converted to a carboxylichalide group or an active ester residue to produce a carboxylic acidhalide or an active ester, and then the compound is allowed to reactwith the amine compound of formula (VII) in an inert solvent, whereby1,4-dihydropyridine derivative of formula (I) can be produced.

The carboxylic acid halide can be produced by a conventional method byallowing the carboxylic acid derivative of formula (VI) in which Z is ahydroxyl group to react with a phosphorous halide such as phosphorouspentachloride, or phosphorous oxychloride; a thionyl halogenide such asthionyl chloride, or thionyl bromide.

The active ester can be produced by a condensation reaction between thecarboxylic acid of formula (VI) and an alcohol such asN-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazol,cyanomethyl alcohol, 2,4-dinitrophenol, 4-nitrophenol, andpentachlorophenol. In this reaction, the previously mentionedcarbodiimides can be employed in the inert solvent.

Furthermore, in the above-mentioned Process 3 the 1,4-dihydropyridinederivatives of formula (I) can be obtained by converting the compoundobtained in any of Process 1, 2 or 3 to the following carboxylic acidderivative of formula (VIII), followed by allowing the carboxylic acidderivative to react with an alcohol compound or an amine compound offormula (IX): ##STR13## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B arerespectively the same as in formula (I).

    R.sup.7 --H                                                (IX)

wherein R⁷ is the same as defined previously.

The above reaction can be carried out under the same conditions by usingthe same solvents as in Process 3 in which the carboxylic acidderivative of formula (VI) and the amine derivative of formula (VII) areallowed to react.

The optically active 1,4-dihydropyridine derivatives of formula (I-a)are produced by any of the following three processes:

Process 4] ##STR14## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and B arerespectively the same as in formula (I), and * indicates a chiralcenter.

[Step A]

The reaction in Step A in the above reaction scheme can be carried outby mixing the keto-ester derivative of formula (X) and the opticallyactive enamine derivative of formula (XI). The optically active enaminederivative of formula (XI) can be easily obtained by allowing acommercially available keto-ester compound to react with an opticallyactive amine compound.

It is preferable to use a basic compound to carry out the reactionefficiently. Examples of the basic compound are n-butyl lithium, lithiumdiisopropylamide, sodium hydride, isopropyl magnesium halide, and phenylmagnesium halide. Such a basic compound is generally employed in anamount of 0.5 to 1.5 equivalents to the keto-ester derivative of formula(X).

Furthermore, it is preferable that the above reaction be carried out ina non-protonic solvent. Examples of the non-protonic solvent are etherssuch as diethyl ether, and tetrahydrofuran, and aromatic hydrocarbonssuch as benzene and toluene.

The reaction proceeds at temperatures of -120° to 110° C., but it ispreferable that the reaction be carried out in the temperature range of-100° C. to -20° C. to cause the reaction to proceed efficiently.

Furthermore, it is preferable that the reaction be carried out under awater-free condition in an atmosphere of an inert gas such as nitrogengas or argon gas in order to obtain the desired product in high yield.

The product obtained by the above reaction is easily decomposed at roomtemperature and therefore difficult to identify. However the product isconsidered to have the following structure from the identification byuse of a mass spectrum: ##STR15## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷,and B are respectively the same as in formula (I), and * indicates achiral center.

The above reaction product is then allowed to react with ammonia or anammonium salt, whereby the optically active cyanoethylester of formula(XII) can be obtained.

The ammonia and the ammonium salt employed in the above reaction arecommercially available. Examples of the ammonium salt are ammoniumacetate, and ammonium chloride.

It is preferable that the ammonia or the ammonium salt be employed in anamount of 1.0 to 20 equivalents, more preferably in an amount of 1.2 to5 equivalents, to the keto-ester derivative of formula (X) in order toobtain the optically active cyanoethyl ester of formula (XII) in highyield. It is also preferable that the reaction with the ammonia or theammonium salt be carried out in a solvent. Examples of the solvent arealcohols such as ethanol, methanol and propanol; ethers such as diethylether and tetrahydrofuran; and hydrocarbons such as hexane, pentane,toluene and benzene.

The reaction proceeds at temperatures of 0° to 60° C., but it ispreferable that the reaction be carried out at room temperature becausethe operations are simple.

Furthermore, the reaction in the above Step A can be carried out byreplacing the keto-ester derivative of formula (X) and the opticallyactive enamine derivative of formula (XI) with a keto-ester derivativeof formula (X') and an enamine derivative of formula (XI') respectively,which are shown below: ##STR16## [Step B]

The reaction in Step B can be carried out by mixing the optically activecyanoethyl ester derivative of formula (XII) with a basic compound.Examples of the basic compound employed in this reaction are sodiummethylate, sodium hydroxide, and potassium hydroxide. It is preferablethat the basic compound be employed in an amount of 1.0 to 3.0equivalents, more preferably in an amount of 1.0 to 1.2 equivalents, tothe optically active cyanoethyl ester derivative of formula (XII), toobtain the product of formula (XIII) in high yield. It is alsopreferable that the reaction be carried out in a solvent, such as water,an alcohol such as methanol, and ethanol, or a mixed solvent of thesesolvents, at temperatures of -20° C. to 80° C., more preferably attemperatures of 0° C. to 25° C. to obtain the product of formula (XIII)in high yield.

[Step C]

The reaction in Step C can be carried out by subjecting the opticallyactive carboxylic acid derivative of formula (XIII) obtained in theabove Step B and the amine compound of formula (VII) to a condensationreaction. This condensation reaction can be carried out in the samereaction temperature range, using the same carbodiimide agent andreaction solvent as in Process 3.

The carboxyl group in the optically active carboxylic acid derivative offormula (XIII) is converted to a carboxylic halide group or an activeester group as in Process 3, and the thus obtained compound is allowedto react with the amine compound of formula (VII), whereby a1,4-dihydropyridine derivative of formula (I) can be obtained. Thisreaction can be carried out in the same reaction temperature range,using the same carbodiimide agent and reaction solvents as in Process 3.

The optically active 1,4-dihydropyridine derivatives of formula (I-a)can be synthesized more efficiently by the following Process 5 andProcess 6 than by the above-mentioned Process 4:

[Process 5]

An N-acylamino acid derivative of formula (XIV) is allowed to react withan optically active enamine derivative of formula (XV) in the followingreaction scheme, followed by allowing the product to react with ammoniaor an ammonium salt: ##STR17## wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R¹⁷,R¹⁸, and B are respectively the same as previously defined, and *indicates a chiral center.

The above reaction can be carried out in the same reaction temperaturerange, using the same reaction solvents as in Step A in Process 4.

[Process 6]

A ketone derivative of formula (XVI) is allowed to react with anoptically active acrylamide derivative of formula (XVII) in thefollowing reaction scheme, followed by allowing the product to reactwith ammonia or an ammonium salt: ##STR18## wherein R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R¹⁷, R¹⁸, and B are respectively the same as previously defined,and * indicates a chiral center.

The above reaction can be carried out in the same reaction temperaturerange, using the same reaction solvents as in Step A in Process 4.

The compounds produced in each of the above processes can be isolated byconventional separation methods, extraction, reprecipitation,recrystallization, and various types of chromatography.

When necessary, the 1,4-dihydropyridine derivatives of formula (I) canbe converted to the corresponding acid-addition salts by the reactionwith pharmaceutically permissible acids. Examples of such acids areinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, and nitric acid; and organic acids such as aceticacid, propionic acid, lactic acid, and citric acid.

When the 1,4-dihydropyridine derivatives of formula (I) are used ashypotensor, vasodilator, cerebral circulation improvement agent,antithrombotic agent, antiasthmatic, antiinflammatory agent, andantiallergic agent, the derivatives can be administered perorally,intravenously, hypodermically, intramuscularly, or by inhalation.Therefore, the derivatives can be used in various administration formsincluding pellet, capsule, liquid, and suppository.

EXAMPLE 1

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:##STR19##

A mixture of 11.2 g (45 mmol) of methyl2-(3-nitrobenzylidene)acetoacetate and 11.53 g (45 mmol) of (s)-t-butyl2-(S)-[N-(3-amino-2-butenoyl)amino]-3-methylbutylate was heated at 110°C. for 20 minutes. After cooling to room temperature, the reactionmixture was chromatographed on a silica gel column for purification,whereby 14.7 g (67.5%) of a diastereo mixture was obtained. Thediastereo mixture was recrystallized from acetonitrile, so that 8.9 g(40.7%) of Compound a of the captioned compound was obtained. The motherliquor was distilled away under reduced pressure and the residue wasrecrystallized from methanol, whereby 5.8 g (27%) of Compound b of thecaptioned compound was obtained.

(Compound a)

Melting point (°C.) 194 (dec.) IR (υKBr, cm⁻¹) 3308, 1716, 1690, 1530,1354 Mass spectrometry Based on Formula C₂₅ H₃₃ N₃ O₇ Calcd. 487.23180Found 487.23146 NMR (δ, CDCl₃) 0.72 (3H, d, J=7 Hz), 0.75 (3H, d, J=7Hz), 1.40 (9H, s), 1.98-2.01 (1H, m), 2.22 (1H, s), 2.35 (3H, s), 3.62(3H, s), 4.39 (1H, dd, J=8 Hz, 4 Hz), 4.99 (1H, s), 5.58 (1H, s), 5.76(1H, d, J=8 Hz), 7.41 (1H, dd, J=8 Hz, 8 Hz), 7.66 (1H, d, J=8 Hz), 8.03(1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁰ =+60.9°(C=1.00, ethanol)

(Compound b)

Melting point (°C.) 157 (dec.) IR (υKBr, cm⁻¹) 3330, 1732, 1714, 1676,1530, 1352 Mass spectrometry Based on Formula C₂₅ H₃₃ N₃ O₇ Calcd.487.23180 Found 487.23299 NMR (δ, CDCl₃) 0.698 (3H, d, J=7 Hz), 0.703(3H, d, J=7 Hz), 1.45 (9H, s), 1.96-2.01 (1H, m), 2.30 (3H, s), 2.33(3H, s), 3.66 (3H, s), 4.42 (1H, dd, J=8 Hz, 4 Hz ), 4.96 (1H, s), 5.59(1H, s), 5.90 (1H, d, J=8 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz ), 7.70 (1H,d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.15 (1H, s) Optical rotation [α]₂₀^(D) =+31.4° (c=100, ethanol)

EXAMPLE 2

Synthesis of t-butyl2-(R)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino-3-methylbutylate:##STR20##

1.65 g (5 mmol) of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid was suspended in 20 ml of dichloromethane. 1.054 g (5.5 mmol) ofhydrochloric acid 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide wasadded to the above suspension in an ice-cooled condition and the mixturewas stirred for one hour.

To the above mixture, a solution of dichloromethane containing 0.952 g(5.5 mmol) of D-valine-t-butylester was added and the mixture wasstirred at room temperature overnight. After washing with water, thereaction mixture was dried over anhydrous sodium sulfate and thedichloro methane was distilled away under reduced pressure. The reactionmixture was chromatographed on a silica gel column for purification,whereby 1.8 g (74%) of a diastereo mixture was obtained. The thusobtained diastereo mixture was recrystallized from acetonitrile, whereby0.525 g (21.5%) of Compound a of the captioned compound was obtained.The mother liquor was distilled away under reduced pressure and theresidue was recrystallized from methanol, whereby 0.05 g (2%) ofCompound b of the captioned compound was obtained.

(Compound a)

Melting point (°C.) 194-196 IR (υKBr, cm⁻¹) 3308, 1718, 1688, 1534, 1354Mass spectrometry Based on Formula C₂₅ H₃₃ N₃ O₇ Calcd. 487.23180 Found487.23174 NMR (δ, CDCl₃) 0.72 (3H, d, J=7 Hz), 0.75 (3H, d, J=7 Hz),1.40 (9H, s), 1.98-2.21 (1H, m), 2.22 (3H, s), 2.35 (3H, s), 3.62 (3H,s), 4.39 (1H, dd, J=9 Hz, 5 Hz), 4.99 (1H, s), 5.54 (1H, s ), 5.76 (1H,d, J=9 Hz), 7.41 (1H, dd, J=8 Hz, 8 Hz), 7.66 (1H, d, J=8 Hz), 8.03 (1H,d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁰ =-32.5° (c=1.00,ethanol)

(Compound b)

Melting point (°C.) 170-173 IR (υKBr, cm⁻¹) 3320, 1734, 1712, 1678,1532, 1352 Mass spectrometry Based on Formula C₂₅ H₃₃ N₃ O₇ Calcd.487.23180 Found 487.23129 NMR (δ, CDCl₃) 0.68 (3H, d, J=7 Hz), 0.71 (3H,d, J=7 Hz), 1.45 (9H, s), 1.97-2.10 (1H, m), 2.30 (3H, s), 2.33 (3H, s),3.66 (3H, s), 4.41 (1H, dd, J=8 Hz, 4 Hz), 4.96 (1H, s), 5.69 (1H, s),5.91 (1H, d, J=8 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.70 (1H, d, J=8 Hz),8.03 (1H, d, J=8 Hz), 8.15 (1H, s) Optical rotation [α]_(D) ²⁰ -60.2°(c=1.00, ethanol)

EXAMPLE 3

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in accordance with the followingreaction scheme by allowing the carboxylic acid employed in Example 2 toreact with an amino acid of formula R¹⁰ --H shown below: ##STR21## theabove formula, R¹⁰ is ##STR22##

Yield (%) 62.5 (recrystallized from acetonitrile) Melting point (° C.)143-146 IR (υKBr, cm⁻¹) 3364, 1718, 1672, 1534, 1352 Mass spectrometryBased on Formula C₂₂ H₂₇ N₃ O₇ Calcd. 445.18484 Found 445.18523 NMR(δ,CDCl₃) 1.43 (9H, s), 2.29 (3H, s), 2.33 (3H, s), 3.65 (3H, s), 3.88(2H, d, J=5 Hz), 4.96 (1H, s), 5.90 (2H, m), 7.42 (1H, dd, J=8 Hz, 8Hz), 7.68 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.13 (1H, s)

EXAMPLE 4

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate:

The above compound was prepared in the same reaction scheme as inExample 3 except that the amino acid employed in Example 3 was replacedby an amino acid of formula R¹⁰ --H, in which R¹⁰ is ##STR23##

Yield (%) 52.5 Melting point (° C.) oil Mass spectrometry Based onFormula C₂₃ H₂₉ N₃ O₇ Calcd. 459.20051 Found 459.20009 IR (υKBr, cm⁻¹)3356, 1678, 1656, 1532, 1350 NMR (δ, CDCl₃) 1.41 (9/2H, s), 1.44 (9/2H,s), 1.26 (3/2H, d, J=7 Hz), 1.28 (3/2H, d, J=7 Hz), 2.25 (3/2H, s), 2.26(3/2H, s), 2.34 (3/2H, s), 2.35 (3/2H, s), 3.64 (3/2H, s), 3.65 (3/2H,s), 4.40 (1/2H, m), 4.42 (1/2H, m), 4.93 (1/2H, s), 4.97 (1/2H, s), 5.66(1/2H, s), 4.93 (1/2H, s), 5.98 (1/2H, d, J=8 Hz), 6.02 (1/2H, d, J=8Hz), 7.41 (1/2H, dd, J=8 Hz, 8 Hz), 7.42 (1/2H, dd, J=8 Hz, 8 Hz), 7.67(1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.13 (1H, s)

EXAMPLE 5

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 3 except that the amino acid employed in Example 3 was replacedby an amino acid of formula R¹⁰ --H, in which R¹⁰ is ##STR24##

Yield (%) 30.5 (recrystallized from acetonitrile) Melting point (° C.)200-203 IR (υKBr, cm⁻¹) 3328, 1746, 1700, 1678, 1532, 1348 Massspectrometry Based on Formula C₂₉ H₃₃ N₃ O₇ Calcd. 535.23181 Found535.23243 NMR (δ, CDCl₃) 1.35 (9H, s), 2.19 (3H, s), 2.33 (3H, s), 2.97(1H, dd, J=15 Hz, 6 Hz), 3.06 (1H, dd, J=15 Hz, 6 Hz), 3.63 (3H, s),4.68-4.76 (1H, m), 4.89 (1H, s), 5.62 (1H, s), 5.73 (1H, d, J=7 Hz),6.90-6.98 (2H, m), 7.18-7.26 (3H, m), 7.36 (1H, dd, J=8 Hz, 8 Hz), 7.52(1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.03 (1H, s)

EXAMPLE 6

Synthesis of t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]pyrrolidine-2-(S)-carboxylate:

The above compound was prepared in the same reaction scheme as inExample 3 except that the amino acid employed in Example 3 was replacedby an amino acid of formula. R¹⁰ --H, in which R¹⁰ is ##STR25##

Yield (%) 72.6 Melting point (° C.) oil IR (υKBr, cm⁻¹) 3320, 1742,1700, 1532, 1350 Mass spectrometry Based on Formula C₂₅ H₃₁ N₃ O₇ Calcd.485.21616 Found 485.21621 NMR (δ, CDCl₃) 1.12-2.72 (4H, m), 1.44 (9/2H,s), 1.45 (9/2H, s), 1.96 (3H, s), 2.38 (3/2H, s), 2.40 (3/2H, s),3.15-3.28 (1/2H, m), 3.41-3.55 (1/2H, m), 3.51 (3/2H, s), 3.60 (3/2H,s), 4.28-4.37 (1H, m), 4.79 (1/2H, s), 5.08 (1/2H, s), 5.57 (1/2H, s),5.69 (1/2H, s), 7.398 (1/2H, dd, J=8 Hz, 8 Hz), 7.403 (1/2H, dd, J=8 Hz,8 Hz), 7.56 (1/2H, d, J=8 Hz), 7.64 (1/2H, d, J=8 Hz), 8.02 (1H, d, J=8Hz), 8.07 (1H, s)

EXAMPLE 7

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]carbamoyl]-3-methylbutylate: ##STR26##

1.60 g (5 mmol) of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carboxylicacid was suspended in 20 ml of dichloromethane. 1.05 g (5.5 mmol) of1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added tothe above suspension in an ice-cooled condition and the mixture wasstirred for one hour. A dichloromethane solution containing 0.952 g (5.5mmol) of L-valine-t-butylester hydrochloride and 0.556 g (5.5 mmol) oftriethylamine was added to the above mixture. The reaction mixture wasrefluxed for 3 days. After washing with water, the reaction mixture wasdried over anhydrous sodium sulfate and the dichloromethane wasdistilled away under reduced pressure. The reaction mixture waschromatographed on a silica gel column for purification, whereby 0.93 g(39%) of a diastereo mixture was obtained. The thus obtained diastereomixture was recrystallized from acetonitrile, whereby 0.15 g (6.2%) ofCompound a of the captioned compound was obtained.

Melting point (° C.) 198-200 IR (υKBr, cm⁻¹) 3324, 1738, 1708 Massspectrometry Based on Formula C ₂₅ H₃₃ ClN₂ O₅ Calcd. 476.20776 Found476.20785 NMR (δ, CDCl₃) 0.69 (6H, d, J=7 Hz), 1.39 (9H, s), 1.92-2.08(1H, m), 2.09 (3H, s), 2.32 (3H, s), 3.56 (3H, s), 4.37 (1H, dd, J=9 Hz,5 Hz), 5.33 (2H, s), 5.70 (1H, d, J=9 Hz), 7.07 (1H, dd, J=8 Hz, 8 Hz),7.18 (1H, d, J=8 Hz), 7.25 (1H, d, J=8 Hz), 7.39 (1H, s)

EXAMPLE 8

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]-amino]acetate:

The above compound was prepared in accordance with the followingreaction scheme by allowing the carboxylic acid employed in Example 7 toreact with an amino acid of formula R¹¹ --H shown below: ##STR27## Inthe above formula, R¹¹ is

Yield (%) 39.5 Melting point (° C.) 116 (dec.) IR (υKBr, cm⁻¹) 3352,1748, 1684 Mass spectrometry Based on Formula C₂₂ H₂₇ ClN₂ O₅ Calcd.434.16080 Found 434.16190 NMR (δCDCl₃) 1.44 (9H, s), 2.22 (3H, s), 2.34(3H, s), 3.59 (3H, s), 3.78 (1H, dd, J=18 Hz, 6 Hz), 3.98 (1H, dd, J=18Hz, 6 Hz), 5.27 (1H, s), 5.65 (1H, s ), 6.23 (1H, t, J=6 Hz ), 7.08 (1H,dd, J=8 Hz, 8 Hz ), 7.18 (1H, dd, J=8 Hz, 8 Hz), 7.24 (1H, d, J=8 Hz),7.42 (1H, d, J=8 Hz)

EXAMPLE 9

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]propionate:

The above compound was prepared in the same reaction scheme as inExample 8 except that the amino acid employed in Example 8 was replacedby an amino acid of formula R¹¹ --H, in which R¹¹ is ##STR28## Yield (%)36 Melting point (° C.) oil IR (υKBr, cm⁻¹) 3328, 1738, 1696 Massspectrometry Based on Formula C₂₃ H₂₉ ClN₂ O₅ Calcd. 448.17646 Found448.17655 NMR (δCDCl₃) 1.23 (3H, d, J=8 Hz), 1.27 (3H, d, J=8 Hz), 1.37(9/2H, s), 1.46 (9/2H, s), 2.12 (3/2H, s), 2.23 (3/2H, s), 2.32 (3/2H,s), 2.33 (3/2H, s), 3.57 (3/2H, s), 3.59 (3/2H, s), 4.34-4.47 (1H, m),5.25 (1/2H, s), 5.27 (1/2H, s), 5.61 (1/2H, s), 5.78 (1/2H, s), 5.88(1/2H, d, J=8 Hz), 6.41 (1/2H, d, J=8 Hz), 7.03-7.12 (1H, m), 7.15-7.28(2H, m), 7.39-7.46 (1H, m)

EXAMPLE 10

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]-amino]-3-phenylpropionate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 8 except that the amino acid employed in Example 8 was replacedby an amino acid of formula R¹¹ --H, in which R¹¹ is ##STR29##

Yield (%) 10.2 (recrystallized from acetonitrile) Melting point (° C.)205-210 IR (υKBr, cm⁻¹) 3344, 1732, 1698, 1676 Mass spectrometry Basedon Formula C₂₉ H₃₃ ClN₂ O₅ Calcd. 524.20776 Found 524.20676 NMR (δ,CDCl₃) 1.33 (9H, s), 2.08 (3H, s), 2.33 (3H, s), 2.88 (1H, dd, J=15 Hz,6 Hz), 3.07 (1H, dd, J=15 Hz, 6 Hz), 3.57 (3H, s), 4.75-4.84 (1H, m),5.33 (1H, s), 5.38 (1H, s), 5.88 (1H, d, J=9 Hz), 6.83-6.90 (2H, m),7.08-7.32 (6H, m), 7.37 (1H, d, J=8 Hz )

EXAMPLE 11

Synthesis of t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]-pyrrolidine-2-(S)-carboxylate:

The above compound was prepared in the same reaction scheme as inExample 8 except that the amino acid employed in Example 8 was replacedby an amino acid of formula R¹¹ --H, in which R¹¹ is ##STR30##

Yield (%) 26 Melting point (° C.) oil IR (υKBr, cm⁻¹) 3288, 1740, 1700Mass spectrometry Based on Formula C₂₅ H₃₁ ClN₂ O₅ Calcd. 474.19211Found 474.19190 NMR (δ, CDCl₃) 1.13-2.50 (5H, m), 1.42 (9/2H, s), 1.45(9/2H, s), 1.87 (3/2H, s), 1.94 (3/2H, s), 2.37 (3H, m), 2.97-3.08(1/2H, m), 3.43-3.82 (1H, m), 3.49 (3/2H, s), 3.53 (3/2H, s), 3.43-3.82(2H, m ), 4.32 (1H, t, J=8 Hz ), 5.24 (1/2H, s), 5.33 (1/2H, s), 5.42(1/2H, s), 5.45 (1/2H, s), 7.02-7.37 (4H, m)

EXAMPLE 12

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)pyridine-3-carbonyl]amino]-4-methylpentanoate:

The above compound was prepared in the same reaction scheme as inExample 8 except that the amino acid employed in Example 8 was replacedby an amino acid of formula R¹¹ --H, in which R¹¹ is ##STR31## Yield (%)27 Melting point (° C.) oil IR (υKBr, cm⁻¹) 3312, 1736, 1690 Massspectrometry Based on Formula C₂₆ H₃₅ ClN₂ O₅ Calcd. 490.22341 Found490.22297 NMR (δ, CDCl₃) 0.77 (3/2H, d, J=6 Hz), 0.78 (3/2H, d, J=6 Hz),0.81 (3/2H, d, J=6 Hz), 0.83 (3/2H, d, J=6 Hz), 1.36 (9/2H, s), 1.46(1/2H, s), 1.08-1.53 (2H, m), 2.14 (3/2H, s), 2.28 (3/2H, s), 2.32(3/2H, s), 2.33 (3/2H, s), 3.57 (3/2H, s), 3.60 (3/2H, s), 4.44 (1H, dt,J=9 Hz, 6 Hz ), 4.49 (1H, dt, J=9 Hz, 6 Hz), 5.26 (1/2H, s), 5.30 (1/2H,s), 5.48 (1/2H, s), 5.62 (1/2H, d, J=9 Hz), 5.66 (1/2H, s), 6.27 (1/2H,d, J=9 Hz), 7.03-7.12 (1H, m), 7.14-7.29 (2H, m), 7.41 (1/2H, d, J=9Hz), 7.44 (1/2H, d, J=9 Hz)

EXAMPLE 13

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-fluorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:##STR32##

A mixture of 1.11 g (5 mmol) of methyl2-(2-fluorobenzylidene)acetoacetate and 1.28 g (5 mmol) of (S)-t-butyl2-[N-(3-amino-2-propenoyl)amino]-3-methylbutylate was refluxed intoluene overnight. After cooling to room temperature, the reactionmixture was chromatographed on a silica gel column for purification,whereby 80 mg (3.5%) of Compound a of the captioned compound, 100 mg(4.3%) of Compound b of the captioned compound and 913 mg (39.8%) of adiastereo mixture were obtained.

(Compound a)

Melting point (°C.) 178 (dec.) IR (υKBr, cm⁻¹) 3292, 1716, 1698 Massspectrometry Based on Formula C₂₅ H₃₃ FN₂ O₅ Calcd. 460.23731 Found460.23726 NMR (δ, CDCl₃) 0.74 (3H, d, J=7 Hz), 0.78 (3H, d, J=7 Hz),1.38 (9H, s), 1.96-2.10 (1H, m), 2.17 (3H, s), 2.32 (3H, s), 3.58 (3H,s), 4.38 (1H, dd, J=9 Hz, 5 Hz), 5.12 (1H, s), 5.42 (1H, s), 5.80 (1H,d, J=9 Hz), 6.95 (1H, ddd, J=10 Hz, 8 Hz, 1 Hz), 7.04 (1H, ddd, J=8 Hz,8 Hz, 1 Hz), 7.14 (1H, dddd, J= 8 Hz, 8 Hz, 5 Hz, 2 Hz), 7.32 (1H, ddd,J=8 Hz, 8 Hz, 2 Hz)

(Compound b)

Melting point (°C.) 113.4-113.7 IR (υKBr, cm⁻¹) 3336, 1734, 1668 Massspectrometry Based on Formula C₂₅ H₃₃ FN₂ O₅ Calcd. 460.23731 Found460.23845 NMR (δ6, CDCl₃) 0.71 (3H, d, J=7 Hz), 0.74 (3H, d, J=7 Hz),1.48 (9H, s), 1.96-2.08 (1H, m), 2.28 (3H, s), 2.32 (3H, s) 3.60 (3H,s), 4.42 (1H, dd, J=8 Hz, 5 Hz), 5.12 (1H, s), 5.94 (1H, s), 6.22 (1H,d, J=8 Hz), 6.93 (1H, ddd, J=10 Hz, 9 Hz, 2 Hz), 7.05 (1H, ddd, J=8 Hz,8 Hz, 2 Hz), 7.06-7.17 (1H, m), 7.36 (1H, ddd, J=8 Hz, 8 Hz, 2 Hz)

EXAMPLE 14

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-trifluoromethylphenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in accordance with the same reactionscheme as in Example 13, except that the ketone compound employed inExample 13 was replaced by a ketone compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR33## wherein R¹²is ##STR34##

Yield (%) 19.2 (recrystallized from acetonitrile) Melting point (°C.)209-212 IR (υKBr, cm⁻¹) 3284, 1718, 1704, 1684 Mass spectrometry Basedon Formula C₂₆ H₃₃ F₃ N₂ O₅ Calcd. 510.23411 Found 510.23128 NMR (δ,CDCl₃) 0.65 (3H, d, J=7 Hz), 0.67 (3H, d, J=7 Hz), 1.43 (9H, s),1.88-2.00 (1H, m), 1.96 (3H, s), 2.35 (3H, s), 3.49 (3H, s), 4.29 (1H,dd, J=9 Hz, 5 Hz), 5.25 (1H, s), 5.35 (1H, s), 5.53 (1H, d, J=9 Hz),7.24 (1H, dd, J=8 Hz, 8 Hz ), 7.48 (1H, dd, J=8 Hz, 8 Hz), 7.52 (1H, d,J=8 Hz), 7.59 (1H, d, J=8 Hz)

EXAMPLE 15

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methoxyphenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR35##

Yield (%) 57.5 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3328, 1734, 1702Mass spectrometry Based on Formula C₂₆ H₃₆ N₂ O₆ Calcd. 471.24947 Found471.24899 NMR (δ, CDCl₃) 0.67 (3/2H, d, J=7 Hz), 0.73 (3/2H, d, J=7 Hz),0.91 (3H, d, J=7 Hz), 1.33 (9/2H, s), 1.48 (9/2H, s), 1.86-2.00 (1/2H,m), 2.02-2.14 (1/2H, m), 2.30 (3/2H, s), 2.32 (3/2H, s), 2 33 (3/2H, s),2.37 (3/2H, s), 3.57 (3/2H, s), 3.58 (3/2H, s), 3.88 (3/2H, s), 3.91(3/2H, s), 4.41 (1H, dd, J=8 Hz, 6 Hz), 5.20 (1/2H, s ), 5.25 (1/2H, s),5.47 (1H, s), 6.67 (1/2H, d, J=8 Hz), 6.78-6.92 (2H, m), 7.07 (1/2H, d,J=8 Hz), 7.09-7.17 (1H, d, J=8 Hz), 7.30-7.36 (1H, m)

EXAMPLE 16

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methylphenyl)pyridine-3-carbonyl]amino]3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR36##

Yield (%) 25.9 (recrystallized from toluene) Melting point (°C.) 174(dec.) IR (υKBr, cm⁻¹) 3296, 1718, 1698 Mass spectrometry Based onFormula C ₂₆ H₃₆ N₂ O₅ Calcd. 456.26238 Found 456.25930 NMR (δ, CDCl₃)0.71 (3H, d, J=7 Hz), 0.81 (3H, d, J=7 Hz), 1.37 (9H, s), 1.97-2.10 (1H,m), 2.21 (3H, s), 2.29 (3H, s), 2.30 (3H, s), 3.63 (3H, s), 4.36 (1H,dd, J=9 Hz, 7 Hz), 4.74 (1H, s ), 5.39 (1H, s), 5.71 (1H, d, J=9 Hz),6.89 (1H, d, J=7 Hz), 7.10-7.15 (3H, m)

EXAMPLE 17

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,4,6-trimethoxyphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR37##

Yield (%) 21.4 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3330, 1734, 1694Mass spectrometry Based on Formula C₂₈ H₄₀ N₂ O₈ Calcd. 532.27842 Found532.27851 NMR (δ, CDCl³) 0.65 (3/2H, d, J=7 Hz), 0.74 (3/2H, d, J=7 Hz),0.90 (3/2H, d, J=7 Hz) 0.93 (3/2H, d, J=7 Hz), 1.31 (9/2H, s), 1.48(9/2H, s), 1.79-1.93 (1/2H, m), 1.97-2.10 (1/2H, m), 2.24 (3H, s), 2.28(3/2H, s), 2.33 (3/2H, s), 3.52 (3/2H, s), 3.53 (3/2H, s), 3.76 (3H, s),3.79 (3H, s), 3.80 (3H, s), 4.38 (1/2H, dd, J=10 Hz, 7 Hz), 4.42 (1/2H,dd, J=10 Hz, 7 Hz), 5.38 (1/2H, s), 5.42 (1/2H, s), 6.07 (1H, s), 6.10(1H, s), 6.78 (1/2H, d, J=9 Hz), 7.19 (1/2H, d, J=9 Hz)

EXAMPLE 18

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR38##

Yield (%) 28.3 (recrystallized from diethyl ether) Melting point (°C.)175 (dec.) IR (υKBr, cm⁻¹) 3320, 1716, 1702, 1684 Mass spectrometryBased on Formula C₂₅ H₃₃ ClN₂ O₅ Calcd. 476.20776 Found 476.20620 NMR(δ, CDCl₃) 0.73 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.40 (9H, s),1.98-2.12 (1H, m), 2.22 (3H, s), 2.32 (3H, s), 3.62 (3H, s), 4.39 (1H,dd, J=9 Hz, 4 Hz), 4.82 (1H, s), 5.42 (1H, s), 5.69 (1H, d, J=9 Hz),7.12 (3H, m), 7.26 (1H, s)

EXAMPLE 19

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-fluorophenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by ketone compound of formula (XVIII) inwhich R¹² is ##STR39##

Yield (%) 28.7 (recrystallized from diethyl ether) Melting point (°C.)169 (dec.) IR (υKBr, cm⁻¹) 3296, 1716, 1702 Mass spectrometry Based onFormula C₂₅ H₃₃ FN₂ O₅ Calcd. 460.23731 Found 460.23785 NMR (δ, CDCl₃)0.73 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.39 (9H, s), 1.99-2.10 (1H,m), 2.21 (3H, s), 2.31 (3H, s), 3.63 (3H, s), 4.38 (1H, dd, J=9 Hz, 5Hz), 4.38 (1H, s), 5.44 (1H, s), 5.69 (1H, d, J=9 Hz), 6.86 (1H, dddd,J=8 Hz, 8 Hz, 2 Hz, 1 Hz), 7.01 (1H, ddd, J=10 Hz, 2 Hz, 1 Hz), 7.10(1H, ddd, J=8 Hz, 2 Hz, 2 Hz), 7.22 (1H, ddd, J=8 Hz, 8 Hz, 6 Hz)

EXAMPLE 20

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-trifluoromethylphenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR40##

Yield (%) 5.1 (recrystallized from acetonitrile) Melting point (°C.) 187(dec.) IR (υKBr, cm⁻¹) 3300, 1720, 1706, 1688 Mass spectrometry Based onFormula C₂₆ H₃₃ F₃ N₂ O₅ Calcd. 510.23410 Found 510.23190 NMR (δ, CDCl₃)0.69 (3H, d, J=7 Hz), 0.73 (3H, d, J=7 Hz), 1.39 (9H, s), 2.21 (1H, s),2.33 (3H, s), 3.61 (3H, s), 4.38 (1H, dd, J=9 Hz, 4 Hz), 4.92 (1H, s),5.44 (1H, s), 5.65 (1H, d, J=9 Hz), 7.37 (1H, dd, J=7 Hz, 7 Hz), 7.43(1H, d, J=7 Hz), 7.52 (1H, d, J=7 Hz), 7.54 (1H, s)

EXAMPLE 21

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-nitrophenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR41##

Yield (%) 43 (recrystallized from toluene) Melting point (°C.) 203(dec.) IR (υKBr, cm⁻¹) 3300, 1716, 1686, 1520, 1348 Mass spectrometryBased on Formula C₂₅ H₃₃ N₃ O₇ Calcd. 487.23181 Found 487.23109 NMR (δ,CDCl₃) 0.74 (3H, d, J=7 Hz), 0.76 (3H, d, J=7 Hz), 1.41 (9H, s),1.99-2.11 (1H, m), 2.21 (3H, s), 2.35 (3H, s), 3.61 (3H, s), 4.40 (1H,dd, J=9 Hz, 4 Hz), 4.99 (1H, s), 5.48 (1H, s), 5.74 (1H, d, J=9 Hz),7.48 (2H, d, J=9 Hz), 8.12 (2H, d, J=9 Hz)

EXAMPLE 22

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-cyanophenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR42##

Yield (%) 3.6 (recrystallized from toluene) Melting point (°C.) 195(dec.) IR (υKBr, cm⁻¹) 3324, 2236, 1730, 1700 Mass spectrometry Based onFormula C₂₆ H₃₃ N₃ O₅ Calcd. 467.24197 Found 467.23961 NMR (δ, CDCl₃)0.69 (6H, d, J=7 Hz), 1.46 (9H, s), 1.97-2.08 (1H, m), 2.30 (3H, s),2.32 (3H, s), 3.66 (3H, s), 4.42 (1H, dd, J=8 Hz, 4 Hz), 4.87 (1H, s),5.56 (1H, s), 5.86 (1H, d, J=8 Hz), 7.36 (1H, dd, J=8 Hz, 8 Hz), 7.46(1H, d, J=8 Hz), 7.59-7.63 (2H, m )

EXAMPLE 23

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methoxyphenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR43##

Yield (%) 60.8 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3330, 1732, 1718,1700, 1682 Mass spectrometry Based on Formula C₂₆ H₃₆ N₂ O₆ Calcd.472.25729 Found 472.25689 NMR (δ, CDCl₃) 0.58 (3/2H, d, J=7 Hz), 0.63(3/2H, d, J=7 Hz), 0.73 (3/2H, d, J=7 Hz), 0.81 (3/2H, d, J=7 Hz), 1.37(9/2H, s), 1.47 (9/2H, s), 1.90-2.12 (1H, m), 2.21 (3/2H, s), 2.28(3/2H, s), 2.29 (3/2H, s), 2.31 (3/2H, s), 3.64 (3/2H, s), 3.67 (3/2H,s), 3.77 (3/2H, s), 3.78 (3/2H, s), 4.33-4.42 (1H, m), 4.76 (1/2H, s),4.78 (1/2H, s), 5.46 (1/2H, s), 5.54 (1/2H, s), 5.73 (1/2H, d, J=8 Hz),5.94 (1/2H, d, J=8 Hz), 6.72 (1H, d, J=8 Hz), 6.89 (1/2H, s), 6.93(1/2H, d, J=8 Hz), 6.95 (1/2H, s), 6.98 (1/2H, d, J=8 Hz), 7.20 (1/2H,dd, J=8 Hz, 8 Hz), 7.21 (1/2H, dd, J=8 Hz, 8 Hz)

EXAMPLE 24

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR44##

Yield (%) 26.9 (recrystallized from diethyl ether) Melting point (°C.)164 (dec.) IR (υKBr, cm⁻¹) 3292, 1718, 1698 Mass spectrometry Based onFormula C₂₅ H₃₃ N₂ O₅ Calcd. 441.23891 Found 441.23902 NMR (δ, CDCl₃)0.70 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.37 (9H, s), 1.95-2.10 (1H,m), 2.22 (3H, s), 2.30 (3H, s), 3.63 (3H, s), 4.36 (1H, dd, J=9 Hz, 5Hz), 4.79 (1H, s), 5.41 (1H, s), 5.67 (1H, d, J=9 Hz), 7.17 (1H, dd, J=7Hz, 7 Hz), 7.26 (2H, dd, J=7 Hz, 7 Hz), 7.33 (2H, d, J=7 Hz)

EXAMPLE 25

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-hydroxyphenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR45##

Yield (%) 18.8 (recrystallized from diethyl ether) Melting point (°C.)170 (dec.) IR (υKBr, cm⁻¹) 3276, 1718, 1676 Mass spectrometry Based onFormula C₂₅ H₃₄ N₂ O₆ Calcd. 458.24163 Found 458.2,4099 NMR (δ, CDCl₃)0.74 (3H, d, J=7 Hz), 0.82 (3H, d, J=7 Hz), 1.39 (9H, s), 1.97-2.11 (1H,m), 2.17 (3H, s), 2.28 (3H, s), 3.63 (3H, s), 4.37 (1H, dd, J=9 Hz, 5Hz), 4.75 (1H, s), 5.53 (1H, s), 5.61 (1H, s), 5.79 (1H, d, J=9 Hz),6.66 (1H, d, J=8 Hz), 6.88 (1H, S), 7.14 (1H, dd, J=8 Hz, 8 Hz)

EXAMPLE 26

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-methoxycarbonyl-4-cyclohexylpyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR46##

Yield (%) 7.7 (recrystallized from diethyl ether) Melting point (°C.)150 (dec.) IR (υKBr, cm⁻¹) 3336, 1718, 1700, 1684 Mass spectrometryBased on Formula C₂₅ H₄₀ N₂ O₅ Calcd. 448.29367 Found 448.29334 NMR (δ,CDCl₃) 0.94 (3H, d, J=7 Hz), 0.96 (3H, d, J=7 Hz), 0.90-1.71 (11H, m),1.49 (9H, s), 2.06-2.22 (1H, m), 2.22 (3H, s), 2.31 (3H, s), 3.65 (1H,d, J=5 Hz), 3.71 (3H, s), 4.52 (1H, dd, J=9 Hz, 5 Hz), 5.38 (1H, s),6.13 (1H, d, J=9 Hz)

EXAMPLE 27

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridine-3-carbonyl]-amino]-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR47##

Yield (%) 8.8 (recrystallized from toluene) Melting point (°C.) 202-204IR (υKBr, cm⁻¹) 3276, 1714, 1686, 1534, 1372 Mass spectrometry Based onFormula C₂₅ H₃₃ N₃ O₇ Calcd. 487.23180 Found 487.23055 NMR (δ, CDCl₃)0.89 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.24 (9H, s), 2.01-2.28 (1H,m), 2.27 (3H, s), 2.44 (3H, s), 3.53 (3H, s), 4.36 (1H, dd, J=8 Hz, 6Hz), 5.60 (1H, s), 5.62 (1H, s ), 7.14 (1H, d, J=8 Hz), 7.28 (1H, dd,J=8 Hz, 8 Hz), 7.49 (1H, dd, J=8 Hz, 8 Hz), 7.59 (1H, d, J=8 Hz), 7.73(1H, d, J=8 Hz)

EXAMPLE 28

Synthesis of t-butyl2-(S)-[N-[4-(2-cyanophenyl)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carbonyl]-amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of the formula shown inExample 14 was replaced by the following ketone in which R¹² in theformula is ##STR48##

Yield (%) 69.7 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3340, 2228, 1740,1710 Mass spectrometry Based on Formula C₂₆ H₃₃ N₃ O₅ Calcd. 467.24198Found 467.24205 NMR (δ, CDCl₃) 0.59 (3/2H, d, J=8 Hz), 0.64 (3/2H, d,J=8 Hz), 0.788 (3/2H, d, J=8 Hz), 0.794 (3/2H, d, J=8 Hz), 1.41 (9/2H,s), 1.44 (9/2H, s), 1.57-1.73 (1/2H, m), 1.91-2.10 (1/2H, m), 2.13(3/2H, s), 2.20 (3/2H, s), 2.32 (3/2H, s), 2.33 (3/2H, s), 3.57 (3/2H,s), 3.62 (3/2H, s), 4.36 (1H, dd, J=8 Hz, 5 Hz), 5.18 (1/2H, s), 5.22(1/2H, s), 5.63 (1/2H, s), 5.67 (1/2H, d, J=8 Hz), 5.71 (1/2H, s), 5.98(1/2H, d, J=8 Hz), 7.20-7.28 (1H, m), 7.43-7.54 (2H, m), 7.57 (1/2H, d,J=8 Hz), 7.61 (1/2H, d, J=8 Hz)

EXAMPLE 29

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methylphenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of the formula shown inExample 14 was replaced by the following ketone in which R¹² in theformula is ##STR49##

Yield (%) 32.0 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3320, 1735, 1700,1680 Mass spectrometry Based on Formula C₂₆ H₃₆ N₂ O₅ Calcd. 456.26238Found 456.26229 NMR (δ, CDCl₃) 0.55 (3/2H, d, J=7 Hz), 0.59 (3/2H, d,J=7 Hz), 0.64 (3/2H, d, J=7 Hz), 0.72 (3/2H, d, J=7 Hz), 1.41 (9/2H, s),1.44 (9/2H, s), 1.52-1.64 (1/2H, m), 1.86-1.98 (1/2H, m), 2.03 (3/2H,s), 2.15 (3/2H, s), 2.30 (3/2H, s), 2.32 (3/2H, s), 2.42 (3/2H, s), 2.50(3/2H, s), 3.53 (3/2H, s), 3.58 (3/2H, s), 4.31 (1/2H, dd, J=9 Hz, 7Hz), 4.35 (1/2H, dd, J=9 Hz, 7 Hz), 5.03 (1/2H, s), 5.10 (1/2H, s), 5.20(1/2H, s), 5.37 (1/2H, s), 5.45 (1/2H, d, J=9 Hz), 5.69 (1/2H, d, J=9Hz), 6.98-7.06 (2H, m), 7.06-7.17 (1H, m), 7.28 (1/2H, d, J=8 Hz), 7.37(1/2H, d, J=8 Hz)

EXAMPLE 30

Synthesis of t-butyl 2-(S)-[N-[1,4-dihydro-5-methoxycarbonyl-2,4,6-trimethylpyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 14 except that the ketone compound of formula (XVIII) employedin Example 14 was replaced by a ketone compound of formula (XVIII) inwhich R¹² is ##STR50##

Yield (%) 55.1 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3330, 1745, 1680,1670 Mass spectrometry Based on Formula C₂₀ H₃₂ N₂ O₅ Calcd. 380.23108Found 380.23095 NMR (δ, CDCl₃) 0.91-1.00 (6H, m), 1.06 (3/2H, d, J=6Hz), 1.07 (3/2H, d, J=6 Hz), 1.48 (9H, s), 1.40-1.50 (1/2H, m),2.15-2.25 (1/2H, m), 2.20 (3/2H, s), 2.21 (3/2H, s), 2.27 (3H, s), 3.65(1H, q, J=7 Hz), 3.72 (3H, s), 4.57 (1H, dd, J=9 Hz, 5 Hz), 5.44 (1H,s), 6.13 (1/2H, d, J=9 Hz), 6.17 (1/2H, d, J=9 Hz)

EXAMPLE 31

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridine-3-carbonyl]amino]acetate:##STR51##

A mixture of 0.498 g (2 mmol) of methyl2-(2-nitrobenzylidene)acetoacetate and 0.428 g (2 mmol) of (s)-t-butyl2-[N-(3-amino-2-butenoyl)amino]acetate was stirred in a light-shieldingcondition at 120° C. for 15 minutes. After cooling to room temperature,the reaction mixture was chromatographed on a silica gel column forpurification, whereby 0.63 g (70.9%) of the captioned compound wasobtained as an oily material.

IR (υKBr, cm⁻¹) 3330, 1746, 1706, 1668, 1528, 1362 Mass spectrometryBased on Formula C₂₂ H₂₇ N₃ O₇ Calcd. 445.18484 Found 445.18513 NMR (δ,CDCl₃) 1.40 (9H, s), 2.28 (3H, s), 2.46 (3H, s), 3.52 (3H, s), 3.75 (1H,dd, J=18 Hz, 5 Hz), 3.98 (1H, dd, J=18 Hz, 5 Hz), 5.55 (1H, s), 5.74(1H, s), 7.29 (1H, dd, J=8 Hz, 8 Hz), 7.46 (1H, t, J=5 Hz), 7.52 (1H,dd, J=8 Hz, 8 Hz), 7.60 (1H, d, J=8 Hz), 7.68 (1H, d, J=8 Hz)

EXAMPLE 32

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in accordance with the same reactionscheme as in Example 31 except that the ketone compound employed inExample 31 was replaced by ketone compound shown below. Specifically thereaction scheme in this example is as follows: ##STR52## wherein R¹² is##STR53## and R¹³ is --CH₃.

Yield (%) 89.8 Melting point (°C.) oil IR (υKBr cm⁻¹) 3268, 1738, 1696,1664 Mass spectrometry Based on Formula C₂₂ H₂₇ ClN₂ O₅ Calcd. 434.16080Found 434.16166 NMR (δ, CDCl₃) 1.44 (9H, s), 2.30 (3H, s), 2.3 (3H, s),3.66 (3H, s), 3.84 (1H, dd, J=18 Hz, 5 Hz), 3.92 (1H, dd, J=18 Hz, 5Hz), 4.80 (1H, s), 5.30 (1H, s), 5.86 (1H, t, J=5 Hz), 7.14-7.29 (4H, m)

EXAMPLE 33

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-cyanophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR54## and R¹³ is --CH₃.

Yield (%) 89.5 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3288, 2228, 1724,1688 Mass spectrometry Based on Formula C₂₃ H₂₇ N₃ O₅ Calcd. 425.19502Found 425.19657 NMR (δ, CDCl₃) 1.43 (9H, S), 2.20 (3H, s), 2.35 (3H, s),3.60 (3H, s), 3.81 (1H, dd, J=18 Hz, 5 Hz), 3.95 (1H, dd, J=18 Hz, 5Hz), 5.18 (1H, s), 5.58 (1H, s), 6.00 (1H, t, J=5 Hz), 7.21-7.26 (4H,m), 7.47-7.50 (2H, m), 7.56 (1H, d, J=8 Hz)

EXAMPLE 34

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-cyanophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR55## and R¹³ is --CH₃.

Yield (%) 91.8 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3352, 2232, 1746,1682 Mass spectrometry Based on Formula C₂₃ H₂₇ N₃ O₅ Calcd. 425.19502Found 425.19391 NMR (δ, CDCl₃) 1.45 (9H, s), 2.29 (3H, s), 2.33 (3H, s),3.65 (3H, s), 3.88 (2H, d, J=5 Hz), 4.87 (1H, s), 5.59 (1H, s), 5.84(1H, t, J=5 Hz), 7.36 (1H, dd, J=8 Hz, 8 Hz), 7.46 (1H, d, J=8 Hz),7.56-7.61 (2H, m)

EXAMPLE 35

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methylphenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR56## and R¹³ is --CH₃.

Yield (%) 60 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3268, 1742, 1694,1666 Mass spectrometry Based on Formula C₂₃ H₃₀ N₂ O₅ Calcd. 414.21543Found 414.21375 NMR (δ, CDCl₃) 1.43 (9H, s), 2.29 (3H, s), 2.31 (3H, s),3.65 (3H, s), 3.78 (1H, dd, J=18 Hz, 5 Hz), 3.91 (1H, dd, J=18 Hz, 5Hz), 4.74 (1H, s), 5.47 (1H, s), 5.94 (1H, t, J=8 Hz), 6.97-7.02 (1H,m), 7.12-7.20 (3H, m)

EXAMPLE 36

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR57## and R¹³ is --C₂ H₅.

Yield (%) 74.2 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1746, 1678,1532, 1350 Mass spectrometry Based on Formula C₂₃ H₂₉ N₃ O₇ Calcd.459.20049 Found 459.19889 NMR (δ, CDCl₃) 1.23 (3H, t, J=7 Hz), 1.43 (9H,s), 2.29 (3H, s), 2.33 (3H, s), 3.87 (2H, d, J=5 Hz), 4.04-4.16 (2H, m),4.96 (1H, s), 5.70 (1H, s), 5.85 (1H, t, J=5 Hz), 7.44 (1H, dd, J=8 Hz,8 Hz), 7.69 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.15 (1H, s)

EXAMPLE 37

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR58## and R¹³ is ##STR59##

Yield (%) 84.9 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1746, 1676,1532, 1350 Mass spectrometry Based on Formula C₂₄ H₃₁ N₃ O₇ Calcd.473.21614 Found 473.21773 NMR (δ, CDCl₃) 1.12 (3H, d, J=6 Hz), 1.25 (3H,d, J=6 Hz), 1.43 (9H, s), 2.28 (3H, s), 2.33 (3H, s), 3.87 (2H, d, J=5Hz), 4.95 (1H, s), 4.92-5.03 (1H, m), 5.66 (1H, s), 5.84 (1H, t, J=5Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.68 (1H, d, J=8 Hz), 8.03 (1H, d, J=8Hz), 8.15 (1H, s)

EXAMPLE 38

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl)-4-(3-nitrophenyl)pyridine-3carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR60## and R¹³ is --(CH₂)₂ --OCH₃.

Yield (%) 79.2 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3340, 1742, 1704,1678, 1528, 1350 Mass spectrometry Based on Formula C₂₄ H₃₁ N₃ O₈ Calcd.489.21106 Found 489.20856 NMR (δ, CDCl₃) 1.43 (9H, s), 2.30 (3H, s),2.34 (3H, s), 3.36 (3H, s), 3.54-3.59 (2H, m), 3.87 (2H, d, J=5 Hz),4.98 (1H, s), 5.59 (1H, s), 5.88 (1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz,8 Hz), 7.72 (1H, d, J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.15 (1H, s)

EXAMPLE 39

Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-4-(3-fluorophenyl)-5-methoxycarbonylpyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR61## and R¹³ is --CH₃.

Yield (%) 62.2 (recrystallized from acetonitrile) Melting point (°C.)107-108 IR (υKBr, cm⁻¹) 3310, 1750, 1695, 1665 Mass spectrometry Basedon Formula C₂₂ H₂₇ FN₂ O₅ Calcd. 418.19036 Found 418.19026 NMR (δ,CDCl₃) 1.44 (9H, s), 2.31 (6H, s), 3.66 (3H, s), 3.84 (1H, dd, J=19 Hz,5 Hz), 3.94 (1H, dd, J=19 Hz, 5 Hz), 4.82 (1H, s), 5.56 (1H, s), 5.87(1H, t, J=5 Hz), 6.87 (1H, dd, J=10 Hz, 8 Hz), 7.01 (1H, d, J=10 Hz),7.13 (1H, d, J=8 Hz), 7.22 (1H, ddd, J=8 Hz, 8 Hz, 6 Hz)

EXAMPLE 40

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-phenylpyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of (XIX) in which R¹² is##STR62## and R¹³ is --CH₃.

Yield (%) 30.0 (recrystallized from acetonitrile) Melting point (°C.)87.5-89.2 IR (υKBr, cm⁻¹) 3300, 1740, 1690, 1660 Mass spectrometry Basedon Formula C₂₂ H₂₈ N₂ O₅ Calcd. 400.19979 Found 400.19990 NMR (δ, CDCl₃)1.44 (9H, s), 2.30 (3H, s), 2.31 (3H, s), 3.66 (3H, s), 3.79 (1H, dd,J=19 Hz), 5 Hz), 3.91 (1H, dd, J=19 Hz, 5 Hz, 4.79 (1H, s), 5.51 (1H,s), 5.89 (1H, t, J=5 Hz), 7.13-7.38 (5H, m)

EXAMPLE 41

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2,4,6-trimethoxyphenyl)pyridine-3-carbonyl]-amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR63## and R¹³ is --CH₃.

Yield (%) 14.3 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3430, 1740, 1695,1670 Mass spectrometry Based on Formula C₂₅ H₃₄ N₂ O₈ Calcd. 490.23147Found 490.23140 NMR (δ, CDCl₃) 1.44 (9H, s), 2.25 (3H, s), 2.32 (3H, s),3.52 (3H, s), 3.60 (1H, dd, J=18 Hz, 5 Hz), 3.77 (3H, s), 3.79 (6H, s),4.10 (1H, dd, J=18 Hz, 5 Hz), 5.37 (1H, s), 5.50 (1H, s), 6.09 (2H, s),7.22 (1H, t, J=5 Hz)

EXAMPLE 42

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-methoxyphenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR64## and R¹³ is --CH₃.

Yield (%) 48.8 (recrystallized from acetonitrile) Melting point (°C.)157.1-159.6 IR (υKBr, cm⁻¹) 3360, 1745, 1700, 1680 Mass spectrometryBased on Formula C₂₃ H₃₀ N₂ O₆ Calcd. 430.21035 Found 430.21041 NMR (δ,CDCl₃) 1.44 (9H, s), 2.29 (3H, s), 2.30 (3H, s), 3.66 (3H, s), 3.79 (3H,s), 3.79 (1H, dd, J=18 Hz, 5 Hz), 3.92 (1H, dd, J=18 Hz, 5 Hz), 4.77(1H, s), 5.54 (1H, s), 5.94 (1H, t, J=5 Hz), 6.74 (1H, d, J=8 Hz), 6.91(1H, s), 6.95 (1H, d, J=8 Hz), 7.20 (1H, dd, J=8 Hz, 8 Hz)

EXAMPLE 43

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5methoxycarbonyl-4-(2-trifluoromethylphenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR65## and R¹³ is --CH₃.

Yield (%) 29.9 (recrystallized from acetonitrile) Melting point (°C.)169-171.6 IR (υKBr, cm⁻¹) 3330, 1750, 1690, 1645 Mass spectrometry Basedon Formula C₂₃ H₂₇ F₃ N₂ O₅ Calcd. 468.18717 Found 468.18720 NMR (δ,CDCl₃) 1.43 (9H, s), 2.01 (3H, s), 2.37 (3H, s), 3.50 (3H, s), 3.78 (1H,dd, J=18 Hz, 5 Hz), 3.90 (1H, dd, J=18 Hz, 5 Hz), 5.19 (1H, s), 5.38(1H, s), 5.63 (1H, t, J=5 Hz), 7.26 (1H, dd, J=8 Hz, 8 Hz), 7.48 (1H,dd, J=8 Hz, 8 Hz), 7.51 (1H, d, J=8 Hz), 7.58 (1H, d, J=8 Hz)

EXAMPLE 44

Synthesis of t-butyl2-[N-[4-cyclohexyl-1,4-dihydro-2,6-dimethyl-5-methoxycarbonylpyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR66## and R¹³ is --CH₃.

Yield (%) 12.3 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3330, 1740, 1680Mass spectrometry Based on Formula C₂₂ H₃₄ N₂ O₅ Calcd. 406.24673 Found406.24668 NMR (δ, CDCl₃) 0.80-1.72 (11H, m), 1.49 (9H, s), 2.25 (3H, s),2.31 (3H, s), 3.59 (1H, d, J=5 Hz), 3.71 (3H, s), 4.01 (2H, d, J=5 Hz),5.42 (1H, s), 6.12 (1H, t, J=5 Hz)

EXAMPLE 45

Synthesis of t-butyl2-[N-[1,4-dihydro-5-methoxycarbonyl-2,4,6-trimethylpyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR67## and R¹³ is --CH₃.

Yield (%) 32.5 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3320, 1750, 1680Mass spectrometry Based on Formula C₁₇ H₂₆ N₂ O₅ Calcd. 338.18414 Found338.18385 NMR (δ, CDCl₃) 1.05 (3H, d, J=7 Hz), 1.49 (9H, s), 2.24 (3H,s), 2.28 (3H, s), 3.62 (1H, q, J=7 Hz), 3.72 (3H, s), 3.96 (1H, dd, J=18Hz, 5 Hz), 4.07 (1H, dd, J=18 Hz, 5 Hz), 5.43 (1H, s), 6.14 (1H, t, J=5Hz)

EXAMPLE 46

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(4-nitrophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 32 except that the ketone compound of formula (XIX) employed inExample 32 was replaced by a ketone compound of formula (XIX) in whichR¹² is ##STR68## and R¹³ is --CH₃.

Yield (%) 49.4 (recrystallized from acetonitrile) Melting point (°C.)157.3-159.1 IR (υKBr, cm⁻¹) 3300, 1750, 1680, 1670, 1520, 1350 Massspectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd. 445.18486 Found445.18469 NMR (δ, CDCl₃) 1.45 (9H, s), 2.30 (3H, s), 2.34 (3H, s), 3.65(3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.54 (1H, s), 5.84 (1H, t,J=5 Hz), 7.49 (2H, d, J=9 Hz), 8.12 (2H, d, J=9 Hz)

EXAMPLE 47

Synthesis of t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-methylphenyl)pyridine-3-carbonyl]amino]acetate:##STR69##

A mixture of 327 mg (1.5 mmol) of methyl2-(2-methylbenzylidene)acetoacetate and 318 g (1.5 mmol) of t-butyl2-[N-(3-amino-2-butenoyl)amino]acetate was stirred in a light-shieldingcondition at 120° C. for 10 minutes. After cooling to room temperature,the reaction mixture was chromatographed on a silica gel column forpurification, whereby 308 mg (49.5%) of the captioned compound wasobtained as an oily material.

IR (υKBr, cm⁻¹) 3332, 1746, 1682 Mass spectrometry Based on Formula C₂₃H₃₀ N₂ O₅ Calcd. 414.21538 Found 414.21498 NMR (δ, CDCl₃) 1.43 (9H, s),2.13 (3H, s), 2.32 (3H, s), 2.46 (3H, s), 3.56 (3H, s), 3.73 (2H, dd,J=18 Hz, 5 Hz), 3.92 (2H, dd, J=18 Hz, 5 Hz), 5.04 (1H, s), 5.34 (1H,s), 5.67 (1H, t, J=5 Hz), 7.02-7.15 (3H, m), 7.33 (1H, d, J=8 Hz)

EXAMPLE 48

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:##STR70## A mixture of 1.95 g (5 mmol) of t-butyl2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]amino]-3-methylbutylate and0.645 g (2 mmol) of ethyl 3-aminocrotonate was stirred in alight-shielding condition at 120° C. for 20 minutes. After cooling toroom temperature, the reaction mixture was chromatographed on a silicagel column for purification, whereby 1.78 g (71.1%) of the captionedcompound was obtained as an oily material.

IR (υKBr, cm⁻¹) 3320, 1736, 1682, 1532, 1352 Mass spectrometry Based onFormula C₂₆ H₃₅ N₃ O₇ Calcd. 501.24746 Found 501.24759 NMR (δ, CDCl₃)0.68-0.75 (6H, m), 1.19 (3/2H, t, J=7 Hz), 1.24 (3/2H, t, J=7 Hz), 1.40(9/2H, s), 1.45 (9/2H, s), 1.97-2.08 (1H, m), 2.22 (3/2H, s), 2.29(3/2H, s), 2.33 (3/2H, s), 2.35 (3/2H, s), 4.02-4.18 (2H, m), 4.13-4.46(1H, m), 4.97 (1/2H, s), 5.00 (1/2H, s), 5.52 (1/2H, s), 5.61 (1/2H, s),5.65 (1/2H, d, J=8 Hz), 5.90 (1/2H, d, J=8 Hz), 7.39 (1/2H, dd, J=8 Hz,8 Hz), 7.42 (1/2H, dd, J=8 Hz, 8 Hz), 7.67 (1/2H, d, J=8 Hz), 7.70(1/2H, d, J=8 Hz), 8.03 (1/2H, s), 8.15 (1/2H, s)

EXAMPLE 49

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino-3-methylbutylate:

The above compound was prepared in accordance with the same reactionscheme as in Example 48, except that the amine compound employed inExample 48 was replaced by an amine compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR71## wherein R¹³is ##STR72##

Yield (%) 58.3 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3324, 1732, 1678,1532, 1352 Mass spectrometry Based on Formula C₂₇ H₃₇ N₃ O₇ Calcd.515.26310 Found 515.26335 NMR (δ, CDCl₃) 0.68-0.74 (6H, m), 1.05 (3/2H,d, J=6 Hz), 1.13 (3/2H, d, J=6 Hz), 1.18 (3/2H, d, J=6 Hz), 1.26 (3/2H,d, J=6 Hz), 1.40 (9/2H, s), 1.44 (9/2H, s), 1.96-2.08 (1H, m), 2.20(3/2H, s), 2.28 (3/2H, s), 2.32 (3/2H, s), 2.34 (3/2H, s), 4.37-4.41(1H, m), 4.88-5.02 (1H, m), 4.96 (1/2H, s), 4.99 (1/2H, s), 5.59 (1/2H,s), 5.68 (1/2H, s), 5.72 (1/2H, d, J=7 Hz), 5.89 (1/2H, d, J=7 Hz), 7.40(1/2H, dd, J=8 Hz, 8 Hz), 7.42 (1/2H, dd, J=8 Hz, 8 Hz), 7.68 (1/2H, d,J=8 Hz), 7.71 (1/2H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.15 (1/2H, s),8.17 (1/2H, s)

example 50

Synthesis of t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl)-4-(3-nitrophenyl)pyridine-3-carbonyl]-amino-3-methylbutylate:(Compound a)

The above compound was prepared in the same reaction scheme as inExample 49 except that the amine compound of formula (XX) employed inExample 49 was replaced by an amine compound of formula (XX) in whichR¹³ is --(CH₂)₂ --OCH₃.

Yield (%) 21.4 (recrystallized from diethyl ether) Melting point (°C.)172.7-174.4 IR (υKBr, cm⁻¹) 3304, 1736, 1682, 1532, 1352 Massspectrometry Based on Formula C₂₇ H₃₇ N₃ O₈ Calcd. 531.25800 Found531.25891 NMR (δ, CDCl₃) 0.69 (3H, d, J=6 Hz), 0.71 (3H, d, J=6 Hz),1.44 (9H, s), 1.96-2.10 (9H, m), 2.30 (3H, s), 2.34 (3H, s), 3.36 (3H,s), 3.53-3.60 (2H, m), 4.12-4.27 (2H, m), 4.39 (1H, dd, J=8 Hz, 4 Hz),4.99 (1H, s), 5.61 (1H, s), 5.93 (1H, d, J=8 Hz), 7.42 (1H, dd, J=8 Hz,8 Hz), 7.75 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.18 (1H, s)

EXAMPLE 51

Synthesis of t-butyl2-(S)-[N-[5[N-(1-(S)-t-butoxy-2-methylpropyl)]carbamoyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine]-3-carbonyl]amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 49 except that the amine compound of formula (XX) employed inExample 49 was replaced by an amine compound of formula (XX) in whichR¹³ is ##STR73##

Yield (%) 60.4 (recrystallized from toluene) Melting point (°C.)204.2-206.2 IR (υKBr, cm⁻¹) 3284, 1732, 1692, 1528, 1350 Massspectrometry Based on Formula C₃₃ H₄₈ N₄ O₈ Calcd. 628.34715 Found628.34579 NMR (δ, CDCl₃) 0.67 (3H, d, J=7 Hz), 0.69 (3H, d, J=7 Hz),0.71 (6H, d, J=7 Hz), 1.41 (9H, s), 1.42 (9H, s), 1.94-2.07 (2H, m),2.17 (3H, s), 2.27 (3H, s), 4.39 (1H, dd, J=8 Hz, 4 Hz), 4.41 (1H, dd,J=8 Hz, 4 Hz), 4.99 (1H, s), 5.25 (1H, s), 5.76 (1H, d, J=8 Hz), 5.87(1H, d, J=8 Hz), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.72 (1H, d, J=8 Hz), 8.03(1H, d, J=8 Hz), 8.18 (1H, s)

EXAMPLE 52

Synthesis of t-butyl2-(S)-[N-[5-(t-butoxycarbonylmethylcarbamoyl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate(Compound a):

The above compound was prepared in the same reaction scheme as inExample 49 except that the amine compound of formula (XX) employed inExample 49 was replaced by an amine compound of formula (XX) in whichR¹³ in the formula is ##STR74##

Yield (%) 31.2 (recrystallized from toluene) Melting point (°C.) 189(dec.) IR (υKBr, cm₋₁) 3332, 1734, 1532, 1350 Mass spectrometry Based onFormula C₃₀ H₄₂ N₄ O₈ Calcd. 586.30020 Found 586.29913 NMR (δ, CDCl₃)0.73 (3H, d, J=7 Hz), 0.74 (3H, d, J=7 Hz), 1.41 (9H, s), 1.42 (9H, s),1.98-2.09 (1H, m), 2.20 (3H, s), 2.28 (3H, s), 3.86 (2H, d, J=5 Hz),4.41 (1H, dd, J=9 Hz, 4 Hz), 4.94 (1H, s), 4.93 (1H, s), 5.31 (1H, s),5.77 (1H, d, J=9 Hz), 5.84 (1H, t, J=5 Hz), 7.44 (1H, dd, J=8 Hz, 8 Hz),7.70 (1H, d, J= 8 Hz), 8.04 (1H, d, J=8 Hz), 8.16 (1H, s)

EXAMPLE 53

Synthesis of t-butyl2-[N-(1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR75##

More specifically, a dioxane solution containing 268 mg (1 mmol) of3-(3-nitrobenzylidene)-3-pyridyl-2-propanone, 1.07 g (5 mmol) of2-[N-(3-amino-2-butenoyl)amino]acetate, 273 mg (2 mmol) of zinc chlorideand 500 mg of Molecular Sieves 4A was refluxed for 2 hours. Aftercooling to room temperature, the reaction mixture was chromatographed ona silica gel column for purification, whereby 401 mg (86%) of2-[N-(1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-pyridylpyridine-3-carbonyl)-amino]acetatewas obtained as an oily material.

IR (υKBr, cm⁻¹) 3320, 1740, 1660, 1530, 1350 Mass spectrometry Based onFormula C₂₅ H₂₈ N₄ O₅ Calcd. 464.20593 Found 464.20581 NMR (δ, CDCl₃)1.42 (9H, s), 1.82 (3H, s), 2.35 (3H, s), 3.87 (2H, d, J=5 Hz), 4.68(1H, s), 5.37 (1H, s), 5.75 (1H, t, J=5 Hz), 7.21 (1H, dd, J=8 Hz, 5Hz), 7.33 (1H, d, J=8 Hz), 7.39 (1H, dd, J=8 Hz, 8 Hz), 7.45 (1H, d, J=8Hz), 8.02 (1H, d, J=8 Hz), 8.08 (1H, s), 8.20 (1H, s), 8.42 (1H, d, J=3Hz)

EXAMPLE 54

Synthesis of methyl1,4-dihydro-2,6-dimethyl-4-(S)-(3-nitrophenyl)-5-[N-[1-(pyrrolidin-1-yl)carbonyl-2-(S)-methylpropyl]carbamoyl]pyridine-3-carboxylate: ##STR76##

309 mg (1.5 mmol) of 1,3-dicyclohexylcarbodiimido was added to a mixtureof 430 mg (1 mmol) of2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutanoic acid, 149 mg (1.1 mmol) of 1-hydroxybenzotriazole, 71 mg(1mmol) of pyrrolidine and 10 ml of dichloromethane in a light-shieldingcondition. The mixture was stirred at room temperature for 4 hours.After washing with water, the reaction mixture was dried over anhydroussodium sulfate. The thus obtained mixture was then chromatographed on asilica gel column for purification, whereby 188 mg (39%) of thecaptioned compound was obtained as an oily material.

IR (υKBr, cm⁻¹) 3264, 1734, 1532, 1352 Mass spectrometry Based onFormula C₂₅ H₃₂ N₄ O₆ Calcd. 484.23213 Found 484.23171 NMR (δ, CDCl₃)0.69 (3H, d, J=7 Hz), 0.83 (3H, d, J=7 Hz), 1.80-1.97 (5H, m), 2.17 (3H,s), 2.35 (3H, s), 3.33-3.50 (4H, m), 3.60 (3H, s), 4.60 (1H, dd, J=9 Hz,6 Hz), 4.99 (1H, s), 5.60 (1H, s), 6.09 (1H, d, J=9 Hz), 7.40 (1H, dd,J=8 Hz, 8 Hz), 7.65 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.10 (1H, s)

EXAMPLE 55

Synthesis of methyl 1,4-dihydro-2,6dimethyl-4-(S)-(3-nitrophenyl)-5-[N-[1-(4-phenylpiperazinyl)carbonyl-2-methylpropyl]carbamoyl]pyridine-3-carboxylate:

The above compound was prepared in accordance with the same reactionscheme as in Example 54, except that the amine compound employed inExample 54 was replaced by an amine compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR77## wherein R¹⁴is ##STR78##

Yield (%) 61.2 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1684, 1532,1350 Mass spectrometry Based on Formula C₃₁ H₃₇ N₅ O₆ Calcd. 575.27432Found 575.27261 NMR (δ, CDCl₃) 0.69 (3H, d, J=7 Hz), 0.83 (3H, d, J=7Hz), 1.83-1.95 (1H, m), 2.20 (3H, s), 2.35 (3H, s), 3.06-3.19 (4H, m),3.55-3.80 (4H, m), 3.61 (3H, s), 4.85 (1H, dd, J=9 Hz, 5 Hz), 5.00 (1H,s), 5.54 (1H, s), 6.14 (1H, d, J=9 Hz), 6.86-6.99 (3H, m), 7.26-7.31(2H, m), 7.40 (1H, dd, J=8 Hz, 8 Hz), 7.65 (1H, d, J=8 Hz), 8.00 (1H, d,J=8 Hz), 8.12 (1H, s )

EXAMPLE 56

Synthesis of methyl 1,4-dihydro-2,6dimethyl-4-(S)-(3-nitrophenyl)-5-[N-[1-(4-diphenylmethylpiperazinyl)carbonyl-2methylpropyl]carbamoyl]pyridine-3-carboxylate:

The above compound was prepared in the same reaction scheme as inExample 55 except that the amine compound employed in Example 55 wasreplaced by an amine compound of formula R₁₄ --H, in which R¹⁴ is##STR79##

Yield (%) 52.6 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3328, 1734, 1532,1350 Mass spectrometry Based on Formula C₃₈ H₄₃ N₅ O₆ Calcd. 665.32127Found 665.32132 NMR (δ, CDCl₃) 0.63 (3H, d, J=7 Hz), 0.76 (3H, d, J=7Hz), 1.74-1.88 (1H, m), 2.16 (3H, s), 2.23-2.42 (4H, m), 2.34 (3H, s),3.36-3.64 (4H, m), 3.59 (3H, s), 4.19 (1H, s), 4.77 (1H, dd, J=9 Hz, 5Hz), 4.98 (1H, s), 5.59 (1H, s), 6.14 (1H, d, J=9 Hz), 7.16-7.31 (6H,m), 7.37-7.42 (5H, m), 7.64 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.10(1H, s)

EXAMPLE 57

Synthesis of methyl1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)-5-[N-[(pyrrolidin-1-yl)carbonylmethyl]carbamoyl]pyridine-3-carboxylate:##STR80##

618 mg (3 mmol) of 1,3-dicyclohexylcarbodiimide was added to a mixtureof 776 mg (2 mmol) of2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3carbonyl]aminoacetic acid, 298 mg (2.2 mmol) of 1-hydroxybenzotriazole, 142 mg (2mmol) of pyrrolidine and 20 ml of dichloromethane in a light-shieldingcondition. The mixture was stirred at room temperature overnight. Afterwashing with water, the reaction mixture was dried over anhydrous sodiumsulfate, whereby 442 mg (50%) of the captioned compound was obtained asan oily material.

IR (υKBr, cm⁻¹) 3336, 1702, 1528, 1348 Mass spectrometry Based onFormula C₂₂ H₂₆ N₄ O₆ Calcd. 442.18519 Found 442.18531 NMR (δ, CDCl₃)1.80-2.03 (4H, m), 2.31 (3H, s), 2.35 (3H, s), 3.34 (2H, t, J=7 Hz),3.47 (2H, t, J=7 Hz), 3.64 (3H, s), 3.87-4.05 (2H, m), 5.00 (1H, s),5.63 (1H, s), 6.53-6.62 (1H, m), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.72 (1H,d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.13 (1H, s)

EXAMPLE 58

Synthesis of methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-[N-[(4-phenylpiperazinyl)carbonylmethyl]carbamoyl]pyridine-3-carboxylate:

The above compound was prepared in accordance with the same reactionscheme as in Example 57, except that an amine compound employed inExample 57 was replaced by an amine compound shown below. Specificallythe scheme in this example is as follows: ##STR81## In the aboveformula, R¹⁴ is ##STR82##

Yield (%) 35.9 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3340, 1676, 1528,1344 Mass spectrometry Based on Formula C₂₈ H₃₁ N₅ O₆ Calcd. 533.22738Found 533.22525 NMR (δ, CDCl₃) 2.32 (3H, s), 2.35 (3H, s), 3.14-3.19(4H, m), 3.51-3.60 (2H, m), 3.64 (3H, s), 3.73-3.82 (2H, m), 4.06 (2H,d, J=4 Hz), 5.00 (1H, s), 5.66 (1H, s), 6.57 (1H, d, J=4 Hz), 6.91-6.96(3H, m), 7.26-7.32 (2H, m), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.71 (1H, d,J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.14 (1H, s)

EXAMPLE 59

Synthesis of methyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-[N-[(4-diphenylmethylpiperazinyl)carbonylmethyl]carbamoyl]pyridine-3-carboxylate:

The above compound was prepared in the same reaction scheme as inExample 58 except that the amine compound employed in Example 58 wasreplaced by an amine compound of formula R¹⁴ --H, in which R¹⁴ is##STR83##

Yield (%) 59.9 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3325, 1658, 1528,1350 Mass spectrometry Based on Formula C₃₅ H₃₇ N₅ O₆ Calcd. 623.27432Found 623.27522 NMR (δ, CDCl₃) 2.26-2.42 (4H, m), 2.30 (3H, s), 2.34(3H, s), 3.33-3.40 (2H, m), 3.54-3.65 (2H, m), 3.63 (3H, s), 3.96 (2H,d, J=4 Hz), 4.23 (1H, s), 4.97 (1H,s), 5.64 (1H, s), 6.56 (1H, t, J=4Hz), 7.16-7.32 (6H, m), 7.35-7.46 (5H, m), 7.69 (1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz), 8.11 (1H, s)

EXAMPLE 60

Synthesis of 2-methoxyethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was prepared in the same reaction scheme as inExample 58 except that the amine compound employed in Example 58 wasreplaced by a compound of formula R¹⁴ --H, in which R¹⁴ is ##STR84##

Yield (%) 48 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3336, 1754, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₁ H₂₅ N₃ O₈ Calcd.447.16408 Found 447.16318 NMR (δ, CDCl₃) 2.30 (3H, s), 2.33 (3H, s),3.37 (3H, s), 3.54-3.63 (2H, m), 3.66 (3H, s), 4.03 (2H, d, J=5 Hz),4.21-4.34 (2H, m), 4.96 (1H, s), 5.80 (1H, s), 5.91 (1H, t, J=5 Hz),7.43 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04 (1H, d, J=8 Hz),8.13 (1H, s)

EXAMPLE 61

Synthesis of ethyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl--methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate: ##STR85##

A mixture of 332 mg (1 mmol) of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid, 309 mg (1.5 mmol) of 1,3-dicyclohexylcarbodiimide, 134 mg (1.1mmol) of 4-dimethylaminopyridine and 10 ml of dichloromethane wasstirred at room temperature for one hour. To the mixture, 174 mg (1.2mmol) of L-valine-t-ethylester was added, and the reaction mixture wasstirred at room temperature overnight. After washing with water, thethus obtained mixture was dried over anhydrous sodium sulfate andchromatographed on a silica gel column for purification, whereby 438 mg(95%) of the captioned compound was obtained.

IR (υKBr, cm⁻¹) 3348, 1746, 1654, 1662, 1532, 1348 Mass spectrometryBased on Formula C₂₃ H₂₉ N₃ O₇ Calcd. 459.20058 Found 459.20218 NMR (δ,CDCl₃) 0.73 (3H, d, J=7 Hz), 0.78 (3H, d, J=7 Hz), 1.21 (3H, t, J=7 Hz),2.00-2.15 (1H, m), 2.24 (3H, s), 2.35 (3H, s), 3.63 (3H, s), 4.04-4.20(2H, m), 4.52 (1H, dd, J=9 Hz, 5 Hz), 4.98 (1H, s), 5.54 (1H, s), 5.74(1H, dd, J=9 Hz), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.67 (1H, d, J=8 Hz),8.05 (1H, d, J=8 Hz), 8.14 (1H, s )

EXAMPLE 62

Synthesis of ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate:

The above compound was prepared in accordance with the same reactionscheme as in Example 61 except that the amine compound employed inExample 61 was replaced by an amine compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR86## wherein R¹⁵is ##STR87##

Yield (%) 75 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1748, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₀ H₂₃ N₃ O₇ Calcd.417.15352 Found 417.15282 NMR (δ, CDCl₃) 1.25 (3H, t, J=7 Hz), 2.31 (3H,s), 2.34 (3H, s), 3.66 (3H, s), 3.98 (2H, d, J=5 Hz), 4.17 (2H, q, J=7Hz), 4.96 (1H, s), 5.83 (1H, s), 5.90 (1H, t, J=5 Hz), 7.43 (1H, dd, J=8Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.14 (1H, s)

EXAMPLE 63

Synthesis of isopropyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]-amino]acetate:

The above compound was prepared in the same reaction scheme as inExample 62 except that the amine compound employed in Example 62 wasreplaced by an amine compound of formula R¹⁵ --H, in which R¹⁵ is##STR88##

Yield (%) 58 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1742, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₁ H₂₅ N₃ O₇ Calcd.431.16924 Found 431.16954 NMR (δ, CDCl₃) 1.225 (3H, t, J=6 Hz), 1.233(3H, d, J=6 Hz), 2.31 (3H, s), 2.34 (3H, s), 3.66 (3H, s), 3.95 (2H, d,J=5 Hz), 4.96 (1H, s), 5.03 (1H, m), 5.83 (1H, s), 5.90 (1H, t, J=5 Hz),7.43 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04 (1H, d, J=8 Hz),8.14 (1H, s)

EXAMPLE 64

Synthesis of ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate:

The above compound was prepared in the same reaction scheme as inExample 62 except that the amine compound employed in Example 62 wasreplaced by an amine compound of formula R¹⁵ --H, in which R¹⁵ is##STR89##

Yield (%) 58 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1736, 1684,1532, 1352 Mass spectrometry Based on Formula C₂₁ H₂₅ N₃ O₇ Calcd.431.16922 Found 431.16641 NMR (δ, CDCl₃) 1.23 (3H, t, J=7 Hz), 2.25 (3H,s), 2.33 (3H, s) 2.38-2.47 (2H, m), 3.38-3.54 3.54 (2H, m), 3.65 (3H,s), 4.07 (2H, d, J=7 Hz), 4.90 (1H, s), 5.64 (1H, s), 6.03 (1H, t, J=6Hz), 7.41 (1H, dd, J=8 Hz, 8 Hz), 7.64 (1H, d, J=8 Hz), 8.03 (1H, d, J=8Hz), 8.11 (1H, s )

EXAMPLE 65

Synthesis of ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl-N-methylamino]acetate:

The above compound was prepared in the same reaction scheme as inExample 62 except that the amine compound employed in Example 62 wasreplaced by an amine compound of formula R¹⁵ --H, in which R¹⁵ is##STR90##

Yield (%) 63 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3320, 1748, 1698,1530, 1352 Mass spectrometry Based on Formula C₂₁ H₂₅ N₃ O₇ Calcd.431.16922 Found 431.16689 NMR (δ, CDCl₃) 1.26 (3H, t, J=7 Hz), 1.93 (3H,s), 2.41 (3H, s), 2.73 (3H, s), 3.56 (3H, s), 3.80-3.94 (1H, m),4.10-4.35 (1H, m), 4.93 (1H, s), 5.46 (1H, s), 7.41 (1H, dd, J=8 Hz, 8Hz), 7.58 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.07 (1H, s )

EXAMPLE 66

Synthesis of t-butyl2-(S)-[N-[[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3carbonyl]amino]acetyl]amino]-3-methylbutylate:##STR91##

In a light-shielding condition, a mixture of 388 mg (1 mmol) of2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxy-carbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]aceticacid, 131 mg (1.3 mmol) of triethylamine and 10 ml of driedtetrahydrofuran was cooled to 0° to 5° C. in an atmosphere of argon gas.To the above mixture, 130 mg (1.2 mmol) of ethyl chlorocarbonate wasadded dropwise and the reaction mixture was stirred for one hour. To thereaction mixture, 225 mg (1.3 mmol) of L-valine-t-butylester was thenadded and the mixture was stirred at room temperature overnight. Thetetrahydrofuran was distilled away under reduced pressure and theresidue was dissolved in dichloromethane. After washing with water, thethus obtained mixture was dried over anhydrous sodium sulfate andchromatographed on a silica gel column for purification, whereby 62 mg(11.4%) of the captioned compound was obtained as an oily material.

IR (υKBr, cm⁻¹) 3330, 1734, 1668, 1532, 1352 Mass spectrometry Based onFormula C₂₇ H₃₆ N₄ O₈ Calcd. 531.25800 Found 531.25891 NMR (δ, CDCl₃)0.85 (3H, d, J=7 Hz), 0.86 (3/2H, d, J=7 Hz), 0.89 (3/2H, d, J=7 Hz),1.44 (9/2H, s), 1.46 (9/2H, s), 2.03-2.19 (1H, m), 2.30 (3H, s), 2.32(3H, s), 3.66 (3H, s), 3.90 (1H, dd, J=17 Hz, 5 Hz), 4.00 (1H, dd, J=17Hz, 5 Hz), 4.38 (1H, dd, J=9 Hz, 5 Hz), 4.97 (1H, s), 6.02-6.16 (1H, m),6.28 (1H, br. s), 6.42-6.58 (1H, m), 7.41 (1H, dd, J=8 Hz, 8 Hz), 7.69(1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.13 (1H, s)

EXAMPLE 67

Synthesis of ethyl1-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]cyclohexanecarboxylate:

The above compound was prepared in accordance with the same reactionscheme as in Example 66 except that the amine compound employed inExample 66 was replaced by an amine compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR92## wherein R¹⁶is ##STR93##

Yield (%) 55 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3340, 1740, 1682,1532, 1350 Mass spectrometry Based on Formula C₂₅ H₃₁ N₃ O₇ Calcd.485.21617 Found 485.21817 NMR (δ, CDCl₃) 0.88-2.02 (10H, m), 1.18 (3H,t, J=7 Hz), 2.26 (3H, s), 2.33 (3H, s), 3.65 (3H, s), 4.05 (2H, m), 4.96(1H, s), 5.38 (1H, s), 5.71 (1H, s), 7.45 (1H, dd, J=8 Hz, 8 Hz), 7.70(1H, d, J=8 Hz), 8.07 (1H, d, J=8 Hz), 8.16 (1H, s)

EXAMPLE 68

Synthesis of ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]isobutyrate:

The above compound was prepared in the same reaction scheme as inExample 66 except that the amine compound of formula R¹⁶ --H employed inExample 66 was replaced by an amine compound of formula R₁₆ --H in whichR¹⁶ is ##STR94##

Yield (%) 60 Melting point (°C.) oil IR (υKBr, cm⁻¹) 3332, 1740, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd.445.18480 Found 445.18340 NMR (δ, CDCl₃) 1.21 (3H, t, J=7 Hz), 1.43 (3H,s), 1.47 (3H, s), 2.22 (3H, s), 2.35 (3H, s), 3.63 (3H, s), 4.07-4.22(2H, m), 4.93 (1H, s), 5.55 (1H, s), 5.91 (1H, s), 7.43 (1H, dd, J=8 Hz,8 Hz), 7.66 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.12 (1H, s)

EXAMPLE 69

Synthesis of ethyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]benzoate:##STR95##

Under an ice-cooled condition, 332 mg (1 mmol) of1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid was suspended in dried dichloromethane. Themixture was stirred with addition of 229 mg (1.1 mmol) of phosphoruspentachloride little by little for one hour. At -30° C., 1650 mg (10mmol) of ethyl anthranilate was added to the reaction mixture. Thereaction mixture was further stirred at room temperature for one hour.After washing with water, the reaction mixture was dried over anhydroussodium sulfate. The thus obtained mixture was chromatographed on asilica gel column for purification, whereby 486 mg (100%) of thecaptioned compound was obtained as an oily material.

IR (υKBr, cm⁻¹) 3336, 1690, 1532, 1350 Mass spectrometry Based onFormula C₂₅ H₂₅ N₃ O₇ Calcd. 479.16920 Found 479.16710 NMR (δ, CDCl₃)1.39 (3H, t, J=7 Hz), 2.36 (3H, s), 2.38 (3H, s), 3.70 (3H, s), 4.35(2H, q, J=7 Hz), 5.26 (1H, s), 5.76 (1H, s), 7.03 (1H, dd, J=8 Hz, 8Hz), 7.38 (1H, dd, J=8 Hz, 8 Hz), 7.48 (1H, dd, J=8 Hz, 8 Hz), 7.71 (1H,d, J=8 Hz), 8.00 (2H, d, J=8 Hz), 8.22 (1H, s), 8.64 (1H, d, J=8 Hz),11.23 (1H, s)

EXAMPLE 70

Synthesis of ethyl3-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]pyrazine-2-carboxylate:##STR96##

The procedure for Example 69 was repeated except that the ethylanthranilate employed in Example 69 was replaced by ethyl3-aminopyrazine-2-carboxylate, whereby the captioned compound wasobtained as an oily material.

IR (υKBr, cm⁻¹) 3316, 1732, 1690, 1530, 1350 Mass spectrometry Based onFormula C₂₃ H₂₃ N₅ O₇ Calcd. 481.15981 Found 481.16061 NMR (δ, CDCl₃)1.45 (3H, t, J=7 Hz), 2.37 (3H, s), 2.48 (3H, s), 3.74 (3H, s), 4.49(2H, q, J=7 Hz), 5.27 (1H, s), 5.99 (1H, s), 7.40 (1H, dd, J=8 Hz, 8Hz), 7.75 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.24 (1H, s), 8.35 (1H,d, J=2.4 Hz), 8.56 (1H, d, J=2.4 Hz), 10.85 (1H, s)

EXAMPLE 71

Synthesis of t-butyl2-[N-[1,4-dihydro-6-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR97##

More specifically, a mixture of 366 mg (0.81 mmol) of t-butyl2-(S)-[N-[2benzoyl-3-(3-nitrophenyl)-2-propenoyl]amino]-3-methylbutylate,95 mg (0.81 mmol) of methyl 3-aminocrotonate and 2 ml of toluene wasrefluxed for 5 hours. After cooling to room temperature, the reactionmixture was chromatographed on a silica gel column for purification,whereby the 198 mg (44%) of a diastereo mixture was obtained as an oilymaterial.

IR (υKBr, cm⁻¹) 3308, 1734, 1704, 1682, 1532, 1352 Mass spectrometryBased on Formula C₃₀ H₃₅ N₃ O₇ Calcd. 549.24747 Found 549.24837 NMR (δ,CDCl₃) 0.36 (3/5H, d, J=7 Hz), 0.40 (12/5H, d, J=7 Hz), 0.44 (3/5H, d,J=7 Hz), 0.55 (12/5H, d, J=7 Hz), 1.27 (36/5H, s), 1.34 (9/5H, s),1.64-1.83 (1H, m), 2.39 (3H, s), 3.63 (3H, s), 4.08 (1H, dd, J=9 Hz, 5Hz), 4.14 (1H, dd, J=9 Hz, 5 Hz), 5.15 (1/5H, s), 5.28 (4/5H, s), 5.36(4/5H, d, J=9 Hz), 5.39 (1/5H, d, J=9 Hz), 6.03 (4/5H, s), 6.10 (1/5H,s), 7.29-7.60 (6H, m), 7.75 (4/5H, d, J=8 Hz), 7.78 (1/5H, d, J=8 Hz),7.90-8.03 (1H, m), 8.22 (4/5H, s), 8.23 (1/5H, s)

Reference Example 1

Synthesis of 2-cyanoethyl methyl1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3,5-dicarboxylate:##STR98##

A toluene solution of 827 mg (3.8 mmol) of 2-cyanoethyl3-amino-3-phenyl-2-propenoate and 952 mg (3.8 mmol) of methyl2-(3-nitrobenzylidene) acetoacetate was refluxed for 3 hours. Thereaction mixture was chromatographed on a silica gel column forpurification, whereby 1.274 g (75%) of the captioned compound wasobtained.

NMR (δ, CDCl₃) 2.16-2.33 (2H, m), 2.41 (3H, s), 3.70 (3H, s), 3.91-4.08(2H, m), 5.23 (1H, s), 5.98 (1H, s), 7.32-7.39 (2H, m), 7.42-7.52 (4H,m), 7.80 (1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.26 (1H, S)

Reference Example 2

Synthesis of 2-cyanoethyl methyl1,4-dihydro-4,6-dimethyl-2-phenylpyridine-3,5-dicarboxylate:

The above compound was prepared in accordance with the same reactionscheme as in Reference Example 1 except that the ketoester derivativeand the enamine derivative employed in Reference Example 1 wererespectively replaced by a ketoester derivative of formula (XXI) and anenamine derivative of formula (XXII) shown below. Specifically thereaction scheme in this example is as follows: ##STR99## wherein R¹⁷ informula (XXI) is --CH₃ and R¹⁸ in formula (XXII) is ##STR100##

Yield (%) 78.9 NMR (δ, CDCl₃) 1.14 (3H, d, J=7 Hz), 2.31 (3H, s ), 2.32(2H, t, J=6 Hz), 3.75 (3H, s ), 3.95 (1H, q, J=7 Hz), 4.03 (1H, ddd,J=11 Hz, 6 Hz, 6 Hz), 4.10 (1H, ddd, J=11 Hz, 6 Hz, 6 Hz), 5.80 (1H, s),7.28-7.35 (2H, m), 7.39-7.48 (3H, m)

Reference Example 3

Synthesis of 2-cyanoethyl methyl1,4-dihydro-2-(2-methoxy-4-methylthiophenyl)-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate:

The above compound was prepared in the same reaction scheme as inReference Example 2 except that the ketoester derivative and the enaminederivative employed in Reference Example 2 were respectively replaced bya ketoester derivative of formula (XXI) in which R¹⁷ is ##STR101## andan enamine derivative of formula (XXII) in which R¹⁸ is ##STR102##

Yield (%) 84.7 NMR (δ, CDCl₃) 2.27 (2H, d, J=6 Hz), 2.36 (3H, s), 2.53(3H, s), 3.72 (3H, s), 3.85 (3H, s), 3.95 (1H, ddd, J=11 Hz, 6 Hz, 6Hz), 4.03 (1H, ddd, J=11 Hz, 6 Hz, 6 Hz), 5.24 (1H, s), 5.91 (1H, s),6.85 (1H, s), 6.87 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.44 (1H, dd,J=8 Hz, 8 Hz), 7.82 (1H, d, J=8 Hz), 8.05 (1H, d, J=8 Hz), 8.36 (1H, S)

Reference Example 4

Synthesis of 2-cyanoethyl methyl2-ethyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate:

The above compound was prepared in the same reaction scheme as inReference Example 2 except that the ketoester derivative and the enaminederivative employed in Reference Example 2 were respectively replaced bya ketoester derivative of formula (XXI) in which R¹⁷ is ##STR103## andan enamine derivative of formula (XXII) in which R¹⁸ is --CH₂ CH₃.

Yield (%) 60.3 NMR (δ, CDCl₃) 1.26 (3H, t, J=7.4 Hz), 2.38 (3H, s), 2.65(2H, t, J=6 Hz), 2.67-2.89 (2H, m), 3.66 (3H, s), 4.19-4.33 (2H, m),5.10 (1H, s), 5.85 (1H, s), 7.40 (1H, dd, J=8 Hz, 8 Hz), 7.67 (1H, d,J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.10 (1H, S)

Reference Example 5

Synthesis of1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylicacid:

The above compound was obtained in accordance with the followingreaction scheme: ##STR104##

More specifically, 557 mg (2.89 mmol) of a 28% sodium methoxide wasadded to a dried mixed solution of methanol and methylene chloride (1:1)containing 1.174 g (2.62 mmol) of 2-cyanoethyl methyl1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3,5-dicarboxylatesynthesized in Reference Example 1. The mixture was stirred at roomtemperature for 2 hours and 100 ml of methylene chloride was addedthereto. The reaction mixture was then extracted with 100 ml of water.The water layer was acidified by 1N hydrochloric acid and extracted withethyl acetate. The ethyl acetate layer was dried over anhydrous sodiumsulfate, and the solvent was distilled away therefrom under reducedpressure, whereby 993 mg t96.2%) of the captioned compound was obtained.

Melting point (°C.) 183.3-185.9 IR (υKBr, cm⁻¹) 3272, 1690, 1670, 1528,1352 NMR (δ, Acetone-d6) 2.47 (3H, s), 3.67 (3H, s), 5.30 (1H, s),7.32-7.48 (5H, m), 7.59 (1H, dd, J=8 Hz, 8 Hz), 7.89 (1H, d, J=8 Hz),8.07 (1H, d, J=8 Hz), 8.23 (1H, s), 8.30 (1H, s), 10.10 (1H, br.S)

Reference Example 6

Synthesis of1,4-dihydro-5-methoxycarbonyl-4,6-dimethyl-2-phenylpyridine-3-carboxylicacid:

The above compound was prepared in accordance with the same reactionscheme as in Reference Example 5 except that the cyanoethyl derivativeemployed in Reference Example 5 was replaced by a cyanoethyl derivativeshown below. Specifically the reaction scheme in this example is asfollows: ##STR105## wherein R¹⁷ is ##STR106## and R¹⁸ is ##STR107##

Yield (%) 61.7 Melting point (°C.) 172.1-175.7 IR (υKBr, cm⁻¹) 3260,1684, 1666 NMR (δ, CD₃ OD) 1.05 (3H, d, J=6 Hz), 2.27 (3H, s), 3.72 (3H,s), 3.87 (1H, q, J=6 Hz), 7.27-7.34 (2H, m), 7.34-7.41 (3H, m)

Reference Example 7

Synthesis of1,4-dihydro-5-methoxycarbonyl-2-(2-methoxy-4-methylthiophenyl)-6-methyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid:

The above compound was prepared in the same reaction scheme as inReference Example 6 except that the cyanoethyl derivative of formula(XXIV) employed in Reference Example 6 was replaced by a cyanoethylderivative of formula (XXIV) in which R¹⁷ is ##STR108## and R¹⁸ is##STR109##

Yield (%) 67 Melting point (°C.) 198.9-201.6 IR (υKBr, cm⁻¹) 3340, 1714,1682, 1530, 1352 NMR (δ, Acetone-d6) 2.39 (3H, s), 2.53 (3H, s), 3.69(3H, s), 3.82 (3H, s), 5.12 (1H, s), 6.84 (1H, d, J=8 Hz), 6.90 (1H, s),7.14 (1H, d, J=8 Hz), 7.56 (1H, dd, J=8 Hz, 8 Hz), 7.92 (1H, d, J=8 Hz),8.04 (1H, d, J=8 Hz), 8.07 (1H, s), 8.39 (1H, s), 9.95 (1H, br.S)

Reference Example 8

Synthesis of2-ethyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)pyridine-3-carboxylate:

The above compound was prepared in the same reaction scheme as inReference Example 6 except that the cyanoethyl derivative of formula(XXIV) employed in Reference Example 6 was replaced by a cyanoethylderivative of formula (XXIV) in which R¹⁷ is ##STR110## and R¹⁸ is --CH₂CH₃.

Yield (%) 96.4 Melting point (°C.) 174.9-176.7 IR (υKBr, cm⁻¹) 3348,1660, 1532, 1352 NMR (δ, Acetone-d6) 1.21 (3H, t, J=7 Hz), 2.37 (3H, s),2.83 (2H, q, J=7 Hz), 3.62(3H, s), 5.19 (1H, s), 7.52 (1H, dd, J=8 Hz, 8Hz), 7.75 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.13 (1H, s), 8.16 (1H,s), 9.95 (1H, br. S)

EXAMPLE 72

Synthesis of t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR111##

More specifically, a dried methylene chloride solution containing 394 mg(1 mmol) of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylate, 309 mg (1.5mmol) of dicyclohexylcarbodiimide and 134 mg (1.1 mmol) ofdimethylaminopyridine was stirred for one hour. To this reactionmixture, 157 mg (1.2 mmol) of glycine t-butyl ester was added and thereaction mixture was refluxed for 2 hours. Insoluble components wereremoved from the reaction mixture by filtration and the reaction mixturewas chromatographed on a silica gel column for purification, whereby 508mg (100%) of the captioned compound was obtained as an oily material.

IR (υKBr, cm⁻¹) 3330, 1742, 1682, 1530, 1350 Mass spectrometry Based onFormula C₂₇ H₂₉ N₃ O₇ Calcd. 507.20051 Found 507.20109 NMR (δ, CDCl₃)1.33 (9H, s), 2.42 (3H, s), 3.54 (1H, dd, J=19 Hz, 5 Hz), 3.67 (3H, s),3.68, (1H, dd, J=19 Hz, 5 Hz), 5.25 (1H, s), 5.32 (1H, t, J=5 Hz), 5.79(1H, s), 7.43 (1H, dd, J=8H, 8 Hz), 7.44-7.51 (5H, m), 7.79 (1H, d, J=8Hz), 8.04 (1H, d, J=8 Hz), 8.25 (1H, S)

EXAMPLE 73

Synthesis of t-butyl2-[N-(1,4-dihydro-5-methoxycarbonyl-4,6-dimethyl-2-phenylpyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in accordance with the same reactionscheme as in Example 72 except that the carboxylic acid derivativeemployed in Example 72 was replaced by a carboxylic acid derivativeshown below. Specifically the reaction scheme in this example is asfollows: ##STR112## wherein R¹⁷ is --CH₃ and R¹⁸ is ##STR113##

Melting point (°C.) 133 (recrystallized from acetonitrile) Yield (%)84.9 IR (υKBr, cm⁻¹) 3296, 1748, 1660 Mass spectrometry Based on FormulaC₂₂ H₂₈ N₂ O₅ Calcd. 400.19979 Found 400.20005 NMR (δ, CDCl₃) 1.16 (3H,d, J=7 Hz), 1.38 (9H, s), 2.32 (3H, s), 3.69 (1H, d, J=18 Hz, 5 Hz),3.79 (1H, dd, J=18 Hz, 5 Hz), 3.72 (3H, s ), 3.90 (1H, q, J=7 Hz), 5.48(1H, t, J=5 Hz), 5.57 (1H, s), 7.36-7.45 (5H, m)

EXAMPLE 74

Synthesis of t-butyl2-[N-(1,4-dihydro-5-methoxy-carbonyl-2-(2-methoxy-4-methylthiophenyl)-6-methyl-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in the same reaction scheme as inExample 73 except that the carboxylic acid derivative of formula (XXVI)employed in Example 73 was replaced by a carboxylic acid derivative offormula (XXVI) in which R¹⁷ is ##STR114## and R¹⁸ is ##STR115##

Melting point (°C.) oil Yield (%) 72 IR (υKBr, cm⁻¹) 3304, 1740, 1682,1532, 1350 Mass spectrometry Based on Formula C₂₉ H₃₃ N₃ O₈ S Calcd.583.19879 Found 583.19700 NMR (δ, CDCl₃) 1.34 (9H, s), 2.34 (3H, s),2.51 (3H, s), 3.56 (1H, dd, J=19 Hz, 5 Hz), 3.67 (1H, dd, J=19 Hz, 5Hz), 3.69 (3H, s), 3.91 (3H, s), 5.29 (1H, s), 5.73 (1H, s), 5.73 (1H,t, J=5 Hz), 6.86 (1H, d, J=7.5 Hz), 6.88 (1H, s), 7.20 (1H, d, J=7.5Hz), 7.41 (1H, dd, J=8H, 8 Hz), 7.82 (1H, d, J=8 Hz), 8.03 (1H, d, J=8Hz), 8.38 (1H, S )

EXAMPLE 75

Synthesis of t-butyl2-[N-(2-ethyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in the same reaction scheme as inExample 73 except that the carboxylic acid derivative of formula (XXVI)employed in Example 73 was replaced by a carboxylic acid derivative offormula (XXVI) in which R¹⁷ is ##STR116## and R¹⁸ is --CH₂ CH₃.

Melting point (°C.) 115 (recrystallized from diethyl ether) Yield (%)74.6 IR (υKBr, cm⁻¹) 3304, 1746, 1682, 1530, 1348 Mass spectrometryBased on Formula C₂₃ H₂₉ N₃ O₇ Calcd. 459.20051 Found 459.20109 NMR (δ,CDCl₃) 1.26 (3H, t, J=7), 1.44 (9H, s), 2.35 (3H s), 2.69 (2H, d, J=7),3.67 (3H, s), 3.87 (2H d, J=5), 4.94 (1H s), 5.71(1H s), 5.86 (1H, t,J=5 Hz), 7.43 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04 (1H, d,J=8 Hz), 8.15 (1H, s )

EXAMPLE 76

Synthesis of t-butyl2-[N-[1,4-dihydro-2-methyl-5-methoxycarbonyl-4-(3-nitrophenyl)-6-phenylpyridine-3-carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR117##

More specifically a mixture of 330 mg (1 mmol) of t-butyl2-[N-[2-acetyl-3-(3-nitrophenyl)-2-propenoyl]amino]acetate and 191 mg (1mmol) of ethyl 3-amino-3-phenyl-2-propenoate was stirred under alight-shielding condition at 110° C. overnight. After cooling to roomtemperature, the reaction mixture was chromatographed on a silica gelcolumn for purification, whereby 98 mg (22%) of the captioned compoundwas obtained as an oily material.

IR (υKBr, cm⁻¹) 3330, 1746, 1682, 1530, 1350 Mass spectrometry Based onFormula C₂₈ H₃₁ N₃ O₇ Calcd. 521.21623 Found 521.21893 NMR (δ, CDCl₃)0.84 (3H, d, J=7 Hz), 1.45 (9H, s), 2.33 (3H, s), 3.75-3.96 (2H, m),3.90 (2H, d, J=5 Hz), 5.07 (1H, s), 5.85 (1H, s), 5.93 (1H, t, J=5 Hz),7.26-7.32 (2H, m), 7.35-7.44 (3H, m), 7.48 (1H, dd, J=8 Hz, 8 Hz), 7.83(1H, d, J=8 Hz), 8.08 (1H, d, J=8 Hz), 8.30 (1H, s)

Reference Example 9

Synthesis of (-)-methyl(R)-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR118##

More specifically, 22.3 mg (0.4 mmol) of acetic acid was added to amixture of 4.31 g (37.1 mol) of methyl acetoacetate and 6.75 g (39 mmol)of R-(-)-valine t-butyl ester, and the mixture was stirred for 24 hours.The reaction mixture was dissolved in 30 ml of anhydrous benzene. Thethus obtained mixture was dried over anhydrous sodium sulfate and thebenzene was distilled away under reduced pressure, whereby 10.07 g(100%) of the captioned compound was obtained.

NMR (δ, CDCl₃) 1.01 (6H, d, J=7 Hz) 1.47 (9H, s), 1.86 (3H, s) 2 09-2.23(1H, m), 3.64 (3H s), 3.78 (1H, dd, J=10 Hz, 6 Hz), 4.52 (1H, s), 8.87(1H, d, J=10 Hz) Optical rotation [α]_(D) ²⁵ =-132° [c=0.95, ethanol]

EXAMPLE 77

Synthesis of (-)-2-cyanoethyl methyl(R)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR119##

More specifically, a tetrahydrofuran solution containingphenylmagnesiumbromide in an amount of 1.2 equivalents was prepared bydissolving 1.30 g (53.4 mg atom) of magnesium, 0.84 g (4.5 mol) of1,2-dibromethane and 6.99 g (44.5 mol) of bromobenzene in 23 ml ofanhydrous tetrahydrofuran. In an atmosphere of argon gas, thetetrahydrofuran solution containing the phenylmagnesiumbromide was addeddropwise to an anhydrous tetrahydrofuran solution containing 10.07 g(37.1 mol) of (-)-methyl(R)-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate at -15° C.and the reaction mixture was stirred for one hour. The reaction mixturewas then cooled to -50° C. and an anhydrous tetrahydrofuran solutioncontaining 10.18 g (35.3 mmol) of 2-cyanoethyl2-(3-nitrobenzylidene)acetoacetate was added dropwise thereto. After thecompletion of the dropwise addition of the tetrahydrofuran solution, thereaction mixture was further stirred for 3 hours. To the reactionmixture, 51.2 ml of 2N hydrochloric acid was added dropwise and thetemperature of the reaction mixture was raised to room temperature. Anorganic layer was separated from the reaction mixture and a water layerwas extracted with tetrahydrofuran. The obtained organic layer and theextracted layer obtained by the tetrahydrofuran were combined and washedwith a saturated aqueous solution of sodium chloride. To an organiclayer obtained from the above mixture, 51.2 ml of 2N hydrochloric acidwas added again and the mixture was stirred at room temperature for 3hours. A saturated aqueous solution of sodium chloride was added to themixture and an organic layer was separated from the mixture and furtherwashed with a saturated aqueous solution of sodium chloride. An organiclayer was separated from the mixture and dried over anhydrous sodiumsulfate. The solvent in the organic layer was distilled away underreduced pressure. The residue was dissolved in 150 ml of methanol. Withaddition of 4.09 g (53 mmol) of ammonium acetate, the residue wasstirred overnight and the solvent was distilled away under reducedpressure. The residue was then dissolved in methylene chloride, washedwith a saturated aqueous solution of sodium hydrogencarbonate and withwater, and dried over anhydrous sodium sulfate. The solvent wasdistilled away under reduced pressure. The residue was recrystallizedfrom 100 ml of methanol, whereby 10.89 g (80%) of the captioned compoundwas obtained.

Melting point (°C.) 165.3°-166.6° C. IR (cm⁻¹,KBr) 3390, 2250, 1706,1682, 1526, 1354 Mass spectrometry Based on Formula C₁₉ H₁₉ N₃ O₆ Calcd.385.12736 Found 385.12672 NMR )δ, CDCl₃) 2.38 (3H, s), 2.40 (3H, s),2.65 (2H, t, J=6 Hz), 3.65 (3H, s), 4.22 (1H, dd, J=13 Hz, 6 Hz), 4.31(1H, dd, J=13 Hz, 6 Hz) , 5.10 (1H, s), 5.77 (1H, s), 7.41 (1H, dd, J=8Hz, 8 Hz), 7.67 (1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.10 (1H, s)Optical rotation [α]_(D) ²⁵ =-20.5° [c=1.038, methanol]

EXAMPLE 78

Synthesis of(+)-(S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR120##

More specifically, under an ice-cooled condition, 10.89 g (28.3 mmol) of(-)-2-cyanoethyl methyl(R)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylatewas suspended in 30 ml of anhydrous methanol. To the mixture, 5.73 g(29.7 mmol) of a 28% sodium methoxide was added. The mixture was stirredat room temperature for one hour and water was added thereto. Thereaction mixture was then washed with methylene chloride. With additionof 2N hydrochloric acid, the pH of the reaction mixture was adjusted to3 to 4, and the reaction mixture was extracted with ethyl acetate. Anorganic layer was separated and washed with water and with a saturatedaqueous solution of sodium chloride, and dried over anhydrous sodiumsulfate. The solvent was distilled away under reduced pressure, whereby9.34 g (100%) of the captioned compound was obtained.

Melting point (°C.) 171°-172° C. (dec.) IR (cm⁻¹, KBr) 3360, 1678, 1534,1352 Mass spectrometry Based on Formula C₁₆ H₁₆ N₂ O₆ Calcd. 332.10081Found 332.10107 NMR (δ, Acetone-d₆) 2.37 (6H, s), 3.61 (3H, s), 5.18(1H, s), 7.52 (1H, t, J=8 Hz), 7.74 (1H, d, J=8 Hz), 8.01 (1H, d, J=8Hz), 8.09 (1H, s), 8.15 (1H, s), 10.4 (1H, s) Optical rotation [α]_(D)²⁵ =+19.3° [c=0.9924, acetone]

EXAMPLE 79

Synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3-yl]carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR121##

More specifically, under a light-shielding condition and in anatmosphere of an inert gas, a methylene chloride solution containing1.91 g (11 mmol) of p-toluenesulfonyl chloride was added dropwise to ananhydrous methylene chloride solution containing 4.39 g (36 mmol) ofN,N-dimethylaminopyridine. The reaction mixture was stirred for one hourunder an ice-cooled condition. To the reaction mixture, 3.32 g (10 mmol)of(+)-(S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylicacid was added and the reaction mixture was stirred for one hour. To thereaction mixture, an anhydrous methylene chloride solution containing1.57 g (12 mmol) of glycine-t-butylester was added dropwise and thereaction mixture was further stirred for one hour. The solvent wasdistilled away under reduce pressure. Toluene was added to the residueand insoluble components were removed from the mixture by filtration.The insoluble components were washed with toluene and the tolueneemployed for the washing was combined with the above filtrate.

The thus obtained toluene solution was washed with a saturated aqueoussolution of ammonium chloride, with a dilute aqueous solution of sodiumhydroxide and then with water, and dried over anhydrous sodium sulfate.The solvent was distilled away from the toluene solution under reducedpressure. The residue was chromatographed on a silica gel column forpurification, whereby 4.00 g (90%) of the captioned compound with anoptical rotation of [α]_(D) ²⁵ =+18.0° (c=1.0031, ethanol) was obtained.

The captioned compound with the following physical properties wasobtained by recrystallization.

Melting point (°C.) 140.9°-142.4° C. IR (cm⁻¹, KBr) υ=3328, 1742, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd.445.18484 Found 445.18726 NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s),2.34 (3H, s), 3.66 (3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62(1H, s), 5.86 (1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d,J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵=+18.3° [c=1.0264, ethanol

EXAMPLE 80

Synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3-yl]carbonyl]amino]acetate:

Under a light-shielding condition and in an atmosphere of an inert gas,3.32 g (10 mmol) of(+)-(S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid was suspended in 33 ml of dried methylene chloride and the abovemixture was cooled to -30° C. To the mixture, 2.29 g (11 mmol) ofphosphorus pentachloride was added and the reaction mixture was stirredat 0° C. for one hour. The reaction mixture was cooled to -30° C. againand a dried methylene chloride solution containing 1.57 g (12 mmol) ofglycine t-butylester and 2.42 g (24 mmol) of triethylamine was added tothe mixture. After stirring at 0° C. for one hour, the reaction mixturewas basified with addition of aqueous ammonia. An organic layer wasseparated from the above mixture and washed with water and dried overanhydrous sodium sulfate. The solvent was distilled away from theorganic solution under reduced pressure. The residue was chromatographedon a silica gel column for purification and then recrystallized, whereby4.23 g (95%) of the captioned compound was obtained. The thus obtainedcompound exhibited the same physical properties as those of the compoundobtained in Example 79.

EXAMPLE 81

Synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3-yl]carbonyl]amino]acetate:

Under a light-shielding condition and in an atmosphere of an inert gas,3.32 g (10 mmol) of(+)-(S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid, 3.09 g (15 mmol) of dicyclohexylcarbodiimide and 4.39 g (36 mmol)of N,N-dimethylaminopyridine were dissolved in 33 ml of dried methylenechloride and the mixture was stirred for one hour. To the above mixture,1.57 g (12 mmol) of glycine t-butylester was added and the mixture wasstirred for 2 days. The insoluble components were removed from themixture by filtration. The solvent was distilled away from the mixtureunder reduced pressure. The residue was chromatographed on a silica gelcolumn for purification and then recrystallized, whereby 4.14 g (93%) ofthe captioned compound was obtained. This obtained compound exhibitedthe same physical properties as those of the compound obtained inExample 79.

EXAMPLE 82

Synthesis of t-butyl2-(R)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-methylbutylate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR122##

More specifically, 354 mg (1.07 mmol) of(S)-(+)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid was suspended in 10 ml of dichloromethane. To the above mixture,330 mg (1.6 mmol) of 1,3-dicyclohexylcarbodiimide and 161 mg (1.3 mmol)of 4-dimethylaminopyridine were added, and the reaction mixture wasstirred for one hour. Subsequently, a dichloromethane solutioncontaining 191 mg (1.1 mmol) of D-valine-t-butylester was added to thereaction mixture and the reaction mixture was stirred at roomtemperature for 2 days. The reaction mixture was washed with water andthen dried over anhydrous sodium sulfate. The dichloromethane wasdistilled away from the reaction mixture under reduced pressure. Thethus obtained mixture was chromatographed on a silica gel column forpurification and then recrystallized from methanol, whereby 340 mg(69.5%) of the captioned compound was obtained. This compound exhibitedthe same physical properties as those of Compound b obtained in Example2.

EXAMPLE 83

Synthesis of (+)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate:

The above compound was synthesized in accordance with the same reactionscheme as in Example 82 except that the amine compound employedin-Example 82 was replaced by an amine compound shown below.Specifically the reaction scheme in this example is as follows:##STR123## wherein R¹⁹ is ##STR124##

Yield (%) 88.2 IR (υKBr, cm⁻¹) 3330, 1740, 1680, 1530, 1350 Massspectrometry Based on Formula C₂₃ H₂₉ N₃ O₇ Calcd. 459.20051 Found459.20035 NMR (δ, CDCl₃) 1.27 (3H, d, J=7 Hz), 1.41 (9H, s), 2.26 (3H,s), 2.36 (3H, s), 3.64 (3H, s), 4.40 (1H, dq, J=7 Hz, 7 Hz), 4.97 (1H,s), 5.55 (1H, s), 5.97 (1H, d, J=7 Hz), 7.41 (1H, dd, J=8 Hz, 8 Hz),7.67 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.13 (1H, s) Opticalrotation [α]_(D) ²⁵ =+71.01° [c=0.9444, ethyl alcohol]

EXAMPLE 84

Synthesis of (+)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate:

The above compound was prepared in the same reaction scheme as inExample 83 except that the amine compound of formula R¹⁹ --H employed inExample 83 was replaced by an amine compound of R¹⁹ --H in which R¹⁹ is##STR125##

Yield (%) 98.1 Melting point (°C.) 200-203 IR (υKBr, cm⁻¹) 3328, 1746,1700, 1678, 1532, 1348 Mass spectrometry Based on Formula C₂₉ H₃₃ N₃ O₇Calcd. 535.23181 Found 535.23243 NMR (δ, CDCl₃) 1.35 (9H, s), 2.19 (3H,s), 2.33 (3H, s), 2.97 (1H, dd, J=15 Hz, 6 Hz), 3.06 (1H, dd, J=15 Hz, 6Hz), 3.63 (3H, s), 4.68-4.76 (1H, m), 4.89 (1H, s), 5.62 (1H, s), 5.73(1H, d, J=7 Hz), 6.90-6.98 (2H, m), 7.18-7.26 (3H, m), 7.36 (1H, dd, J=8Hz, 8 Hz), 7.52 (1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.03 (1H, s)Optical rotation [α]_(D) ²⁵ =+33.35° [c=0.993, ethyl alcohol]

EXAMPLE 85

Synthesis of (+)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-methylpentanoate:

The above compound was synthesized in the same reaction scheme as inExample 83 except that the amine compound of formula R¹⁹ --H employed inExample 83 was replaced by an amine compound of R¹⁹ --H in which R¹⁹ is##STR126##

Yield (%) 99.2 IR (υKBr, cm⁻¹) 3320, 1740, 1690, 1530, 1350 Massspectrometry Based on Formula C₂₆ H₃₅ N₃ O₇ Calcd. 501.24746 Found501.24722 NMR (δ, CDCl₃) 1.16-1.62 (3H, m), 1.40 (9H, s), 2.23 (3H, s),2.35 (3H, s), 3.61 (3H, s), 4.48 (1H, dt, J=8 Hz, 5 Hz), 5.01 (1H, s),5.48 (1H, s), 5.61 (1H, d, J=8 Hz), 7.40 (1H, dd, J=8 Hz, 8 Hz), 7.65(1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.12 (1H, s) Optical rotation[α]_(D) ²⁵ =+90.65° [c=0.9869, ethyl alcohol]

EXAMPLE 86

Synthesis of (+)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-(t-butoxycarbonyl)butylate:

The above compound was synthesized in the same reaction scheme as inExample 83 except that the amine compound of formula R¹⁹ --H employed inExample 83 was replaced by an amine compound of formula R¹⁹ --H in whichR¹⁹ is ##STR127##

Yield (%) 97.8 IR (υKBr, cm⁻¹) 3330, 1730, 1710, 1680, 1530, 1350 Massspectrometry Based on Formula C₂₉ H₃₉ N₃ O₉ Calcd. 573.26858 Found573.26850 NMR (δ, CDCl₃) 1.40 (9H, s), 1.43 (9H, s), 1.73-2.15 (4H, m),2.26 (3H, s), 2.36 (3H, s), 3.63 (3H, s), 4.45 (1H, dt, J=7 Hz, 4 Hz)5.00 (1H, s), 5.51 (1H, s), 6.09 (1H, d, J=7 Hz), 7.41 (1H, dd, J=8 Hz,8 Hz), 7.67 (1H, d, J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.14 (1H, S) Opticalrotation [α]_(D) ²⁵ =+73.76° [c=1.0150, ethyl alcohol]

EXAMPLE 87

Synthesis of (+)-t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]pyrrolidine-2-(S)-carboxylate:

The above compound was synthesized in the same reaction scheme as inExample 83 except that the amine compound of formula R¹⁹ --H employed inExample 83 was replaced by an amine compound of formula R¹⁹ --H in whichR¹⁹ is ##STR128##

Yield (%) 86.0 IR (υKBr, cm⁻¹) 3320, 1740, 1700, 1532, 1350 Massspectrometry Based on Formula C₂₅ H₃₁ N₃ O₇ Calcd. 485.21616 Found485.21630 NMR (δ, CDCl₃) 1.45 (9H, s), 1.63-1.84 (3H, m), 1.97 (3H, s)2.05-2.18 (1H, m), 2.41 (3H, s), 2.62-2.70 (1H, m), 3.15-3.27 (1H, m),3.51 (3H, s), 4.32 (1H, t, J=8 Hz), 5.08 (1H, s), 5.37 (1H, s), 7.39(1H, dd, J=8 Hz, 8 Hz), 7.55 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.07(1H, s) Optical rotation [α]_(D) ²⁵ =+10.15° [c=1.0076, ether alcohol]

Reference Example 10

Synthesis of (+)-methyl(S)-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR129##

More Specifically, 22.3 mg (0.4 mmol) of acetic acid was added to amixture of 4.31 g (37.1 mol) of methyl acetoacetate and 6.75 g (39 mmol)of 1-valine t-butyl ester, and the obtained mixture was stirred for 24hours. The reaction mixture was dissolved in 30 ml of anhydrous benzeneand dried over anhydrous sodium sulfate. The benzene was distilled awayfrom the reaction mixture under reduced pressure, whereby 10.07 g (100%)of the captioned compound was obtained.

NMR (δ, CDCl₃) 1.01 (6H, d, J=7 Hz), 1.47 (9H, s), 1.86 (3H, s),2.09-2.23 (1H, m), 3.64 (3H, s), 3.78 (1H, dd, J=10 Hz, 6 Hz), 4.52 (1H,s), 8.87 (1H, d, J=10 Hz) Optical rotation [α]_(D) ²⁵ =+132° [c=1.01,ethanol]

EXAMPLE 88

Synthesis of (+)-2-cyanoethyl methyl(S)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR130##

More specifically, a tetrahydrofuran solution containingphenylmagnesiumbromide in an amount of 1.2 equivalents was prepared bydissolving 1.30 g (53.4 mg atom) of magnesium, 0.84 g (4.5 mol) of1,2-dibromoethane and 6.99 g (44.5 mol) of bromobenzene in 23 ml ofanhydrous tetrahydrofuran. In an atmosphere of argon gas, thetetrahydrofuran solution containing the phenylmagnesiumbromide was addeddropwise to an anhydrous tetrahydrofuran solution containing 10.07 g(37.1 mol) of (+)-methyl(S)-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate at -15° C.and the reaction mixture was stirred for one hour. The reaction mixturewas cooled to -50° C. and an anhydrous tetrahydrofuran solutioncontaining 10.18 g (35.3 mmol) of 2-cyanoethyl2-(3-nitrobenzylidene)acetoacetate was added dropwise to the abovereaction mixture. After the completion of the dropwise addition of thetetrahydrofuran solution, the reaction mixture was further stirred for 3hours.

To the reaction mixture, 51.2 ml of 2N hydrochloric acid was addeddropwise and the temperature of the reaction mixture was raised to roomtemperature. An organic layer was separated from the reaction mixtureand a water layer was extracted with tetrahydrofuran. The obtainedorganic layer and the extracted layer obtained by the tetrahydrofuranwere combined and washed with a saturated aqueous solution of sodiumchloride. To an organic layer obtained from the above mixture, 51.2 mlof 2N hydrochloric acid was added again and the mixture was stirred atroom temperature for 3 hours. A saturated aqueous solution of sodiumchloride was added to the mixture and an organic layer was separatedfrom the mixture and further washed with a saturated aqueous solution ofsodium chloride. An organic layer was separated from the mixture anddried over anhydrous sodium sulfate. The solvent in the organic layerwas distilled away under reduced pressure. The residue was dissolved in150 ml of methanol. With addition of 4.09 g (53 mmol) of ammoniumacetate, the residue was stirred overnight and the solvent was distilledaway under reduced pressure. The residue was then dissolved in methylenechloride, washed with a saturated aqueous solution of sodiumhydrogencarbonate and then with water, and dried over anhydrous sodiumsulfate. The solvent was distilled away under reduced pressure. Theresidue was recrystallized from 100 ml of methanol, whereby 10.89 g(80%) of the captioned compound was obtained.

Melting point (°C.) 165.3°-166.6° C. IR (cm⁻¹, KBr) 3388, 2250, 1706,1682, 1526, 1354 Mass spectrometry C₁₉ H₁₉ N₃ O₆ Calcd. 385.12736 Found385.12672 NMR (δ, CDCl₃) 2.38 (3H, s), 2.40 (3H, s), 2.65 (2H, t, J=6Hz), 3.65 (3H, s), 4.22 (1H, dd, J=13 Hz, 6 Hz), 4.31 (1H, dd, J=13 Hz,6 Hz), 5.10 (1H, s), 5.77 (1H, s), 7.41 (1H, t, J=8 Hz), 7.67 (1H, d,J=8 Hz), 8.02 (1H, d, J=8 Hz), 8.10 (1H,s) Optical rotation [α]_(D) ²⁵=+20.5° [c=1.005, methanol]

EXAMPLE 89

Synthesis of(-)-(R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylicacid:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR131##

More specifically, under an ice-cooled condition, 10.89 g (28.3 mmol) of(+)-2-cyanoethyl methyl(S)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylatewas suspended in 30 ml of anhydrous methanol. To the above mixture, 5.73g (29.7 mmol) of a 28% sodium methoxide was added. The reaction mixturewas stirred at room temperature for one hour and water was addedthereto. The reaction mixture was then washed with methylene chloride.With addition of 2N hydrochloric acid, the PH of the reaction mixturewas adjusted to 3 to 4, and the reaction mixture was extracted withethyl acetate. An organic layer was separated and washed with water andthen with a saturated aqueous solution of sodium chloride, and driedover anhydrous sodium sulfate. The solvent was distilled away underreduced pressure, whereby 9.34 g (100%) of the captioned compound wasobtained.

Melting point (°C.) 171°-172° C. (dec.) IR (cm⁻¹, KBr) 3360, 1678, 1534,1352 Mass spectrometry C₁₆ H₁₆ N₂ O₆ Calcd. 332.10081 Found 332.10107NMR (δ, Acetone-d₆) 2.37 (6H, s), 3.61 (3H, s), 5.18 (1H, s), 7.52 (1H,t, J=8 Hz), 7.74 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.09 (1H, s),8.15 (1H, s), 10.4 (1H, s). Optical rotation [α]_(D) ²⁵ =-19.3°[c=1,021, acetone]

EXAMPLE 90

Synthesis of (-)-t-butyl(R)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR132##

More specifically, under a light-shielding condition and in anatmosphere of an inert gas, a methylene chloride solution containing 191g (11 mmol) of p-toluenesulfonylchloride was added dropwise to ananhydrous methylene chloride solution containing 4.39 g (36 mmol) ofN,N-dimethylaminopyridine under an ice-cooled condition. The abovereaction mixture was stirred for one hour. To the reaction mixture, 3.32g (10 mmol) of(-)-(R)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3carboxylicacid was added and the reaction mixture was stirred for one hour. To themixture, an anhydrous methylene chloride solution containing 1.57 g (12mmol) of glycine-t-butylester was added dropwise and the reactionmixture was further stirred for one hour. The solvent was distilled awayfrom the reaction mixture under reduced pressure and toluene was addedto the obtained residue. Insoluble components were removed from themixture by filtration. The insoluble components were washed with tolueneand the toluene employed for the washing was combined with the abovefiltrate. The mixture was successively washed with a saturated aqueoussolution of ammonium chloride, with a dilute aqueous solution of sodiumhydroxide and water, and dried over anhydrous sodium sulfate. Thesolvent was distilled away under reduced pressure. The thus obtainedresidue was chromatographed on a silica gel column for purification,whereby 3.96 g (89%) of the captioned compound with an optical rotationof [α]_(D) ²⁵ =-18.1° (c=1.102, ethanol) was obtained. The captionedcompound with the following physical properties was obtained byrecrystallization.

Melting point (°C.) 140.0°-141.8° C. IR (cm⁻¹, KBr) υ=3328, 1742, 1682,1532, 1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd.445.18484 Found 445.18655 NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s),2.34 (3H, s), 3.66 (3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62(1H, s), 5.86 (1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d,J=8 Hz), 8.04 (1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵=-18.4° [c=1.053, ethanol]

EXAMPLE 91

Synthesis of (-)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]propionate:

The above compound was synthesized in accordance with the same reactionscheme as in Example 90 except that the amine compound employed inExample 90 was replaced by an amine compound shown below. Specificallythe reaction scheme in this example is as follows: ##STR133## whereinR¹⁹ is ##STR134##

Yield (%) 90.8 IR (cm⁻¹, υKBr) 3320, 1740, 1680, 1530, 1350 Massspectrometry Based on Formula C₂₃ H₂₉ N₃ O₇ Calcd. 459.20051 Found459.20040 NMR (δ, CDCl₃) 1.26 (3H, d, J=7 Hz), 1.45 (9H, s), 2.26 (3H,s), 2.35 (3H, s), 3.65 (3H, s), 4.42 (1H, dq, J=7 Hz, 4 Hz), 4.93 (1H,s), 5.58 (1H, s), 5.99 (1H, d, J=7 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz),7.67 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.12 (1H, s) Opticalrotation [α]_(D) ²⁵ =-31.24° [c=1.0188, ethyl alcohol]

EXAMPLE 92

Synthesis of (-)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-3-phenylpropionate:

The above compound was synthesized in the same reaction scheme as inExample 91 except that the amine compound of formula (XXVIII) employedin Example 91 was replaced by an amine compound of formula (XXVIII) inwhich R¹⁹ is ##STR135##

Yield (%) 100 IR (cm⁻¹, KBr ) 3330, 1740, 1690, 1530, 1350 Massspectrometry Based on Formula C₂₉ H₃₃ N₃ O₇ Calcd. 535.23181 Found535.23190 NMR (δ, CDCl₃) 1.41 (9H, s), 2.23 (3H, s), 2.31 (3H, s), 2.95(1H, dd, J=15 Hz, 6 Hz), 3.03 (1H, dd, J=15 Hz, 6 Hz), 3.65 (3H, s),4.72 (1H, dt, J=8 Hz, 6 Hz), 4.87 (1H, s), 5.63 (1H, s), 5.79 (1H, d,J=8 Hz), 6.86-6.92 (2H, m), 7.06-7.14 (3H, m) 7.35 (1H, dd, J=8 Hz, 8Hz), 7.56 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz), 8.05 (1H, s) Opticalrotation [α].sub. D²⁵ =-23.61° [c=1.0035, ethyl alcohol]

EXAMPLE 93

Synthesis of (-)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]amino]-4-methylpentanoate:

The above compound was synthesized in the same reaction scheme as inExample 91 except that the amine compound of formula (XXVIII) employedin Example 91 was replaced by an amine compound of formula (XXVIII) inwhich R¹⁹ is ##STR136##

Yield (%) 99.8 IR (υcm⁻¹, KBr) 3330, 1740, 1690, 1630, 1540, 1350 Massspectrometry Based on Formula C₂₆ H₃₅ N₃ O₇ Calcd. 501.24746 Found501.24752 NMR (δ, CDCl₃) 0.77 (3H, d, J=6 Hz), 0.79 (3H, d, J=6 Hz),1.20-1.57 (3H, m), 1.44 (9H, s), 2.28 (3H, s), 2.34 (3H, s), 3.66 (3H,s), 4.46 (1H, dt, J=8 Hz, 6 Hz) , 4.94 (1H, s), 5.65 (1H, s), 5.77 (1H,d, J=8 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.67 (1H, d, J=8 Hz), 8.04 (1H,d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵ =-24.65° [c=0.9926,ethyl]

EXAMPLE 94

Synthesis of (-)-t-butyl2-(S)-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3carbonyl]amino]-4-(t-butoxycarbonyl)butylate:

The above compound was synthesized in the same reaction scheme as inExample 91 except that the amine compound of formula (XXVIII) employedin Example 91 was replaced by an amine compound of formula (XXVIII) inwhich R¹⁹ is ##STR137##

Yield (%) 65.3 IR (υcm⁻¹, KBr) 3320, 1730, 1710, 1680, 1530, 1350 Massspectrometry Based on Formula C₂₉ H₃₉ N₃ O₉ Calcd. 573.26858 Found573.26863 NMR (δ, CDCl₃) 1.40 (9H, s), 1.45 (9H, s), 1.70-2.23 (4H, m),2.30 (3H, s), 2.34 (3H, s), 3.65 (3H, s), 4.46 (1H, dt, J=7 Hz, 4 Hz),4.94 (1H, s), 5.65 (1H, s), 6.17 (1H, d, J=7 Hz), 7.42 (1H, dd, J=8 Hz,8 Hz), 7.69 (1H, d, J=8 Hz), 8.03 (1H, d, J=8 Hz), 8.15 (1H, S) Opticalrotation [α]_(D) ²⁵ =-15.01° [c=0.8836, ethyl alcohol]

EXAMPLE 95

Synthesis of (-)-t-butyl1-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(R)-(3-nitrophenyl)pyridine-3-carbonyl]pyrrolidine-2-(S)-carboxylate:

The above compound was synthesized in the same reaction scheme as inExample 91 except that the amine compound of formula (XXVIII) employedin Example 91 was replaced by an amine compound of formula (XXVIII) inwhich R¹⁹ is ##STR138##

Yield (%) 89.5 IR (υcm⁻¹, KBr) 3270, 1740, 1694, 1530, 1350 Massspectrometry Based on Formula C₂₅ H₃₁ N₃ O₇ Calcd. 485.21616 Found485.21590 NMR (δ, CDCl₃) 1.44 (9H, s), 1.75-2.00 (3H, m), 1.97 (3H, s),2.12-2.26 (1H, m), 2.38 (3H, s), 3.16-3.27 (1H, m), 3.43-3.60 (1H, m),3.60 (3H, s), 4.31 (1H, dd, J=8 Hz, 3 Hz), 4.79 (1H, s), 5.54 (1H, s),7.40 (1H, dd, J=8 Hz, 8 Hz), 7.63 (1H, d, J=8 Hz), 8.01 (1H, d, J=8 Hz),8.07 (1H, s,) Optical rotation [α]_(D) ²⁵ =-39.09° [c= 1.0060, ethylalcohol]

Reference Example 11

Synthesis of t-butyl 2-[N-(3-oxobutanoyl)amino]acetate: 3.93 g (50 mmol)of t-butyl 2-aminoacetate was dissolved in 65 ml of benzene. To theabove mixture, 4.41 g (52.5 mmol) of diketene was added dropwise and thereaction mixture was stirred for one hour. The reaction mixture waswashed with a saturated aqueous solution of sodium hydrogencarbonate andthen with water, and dried over anhydrous sodium sulfate. The solventwas distilled away from the reaction mixture under reduced pressure,whereby 9.821 g (91.2%) of the captioned compound was obtained.

NMR (δ, CDCl₃) 1.47 (9H, s), 2.28 (3H, s), 3.46 (2H, s), 3.96 (2H, d,J=5 Hz), 7.33 (1H, s )

Reference Example 12

Synthesis of t-butyl2-[N-[2-(3-nitrobenzylidene)-3-oxobutanoyl]amino]acetate:

9,821 g (45.6 mmol) of t-butyl 2-[N-(3-oxobutanoyl)amino]acetate and6,891 g (45.6 mmol) of 3-nitrobenzaldehyde were suspended in 50 ml ofisopropyl alcohol. With addition of 0.331 g (2.28 mmol) of piperidineacetate, the mixture was stirred for 15 hours. The above mixture wasice-cooled for one hour and the precipitated crystals were separated byfiltration. The thus obtained crystals were washed with cooled isopropylalcohol and dried under reduced pressure. The thus obtained crystalswere recrystallized from acetonitrile, whereby 13.5 g (85%) of thecaptioned compound was obtained.

Melting point (°C.) 104.8-106.0 NMR (δ, CDCl₃) 1.46 (9H, s), 2.50 (3H,s), 4.08 (2H, d, J=5 Hz), 6.47 (1H, d, J=5 Hz), 7.58 (1H, t, J=8 Hz),7.60 (1H, s), 7.90 (1H, d, J=8 Hz), 8.24 (1H, d, J=8 Hz), 8.38 (1H, s )

Reference Example 13

Synthesis of (-)-methyl(R)-[N-[1-(t-butoxycarbonyl)-2-methypropyl]]aminocrotonate:

0.018 g (0.3 mol) of acetic acid was added to a mixture of 3.484 g (30mmol) of methyl acetoacetate and 5.458 g (31.5 mmol) of D-valine t-butylester. The above mixture was then stirred for 24 hours and dissolved in45 ml of benzene. The reaction mixture was washed with water and driedover anhydrous sodium sulfate. The solvent was distilled away from thereaction mixture under reduced pressure, whereby 8.14 g (100%) of thecaptioned compound was obtained. Optical rotation [α]=-132° [c=0.95,ethanol ] NMR (δ, CDCl₃) 1.01 (6H, d, J=7 Hz), 1.47 (9H, s), 1.86 (3H,s), 2.09-2.23 (1H, m), 3.64 (3H, s), 3.78 (1H, dd, J=10 Hz, 6 Hz), 4.52(1H, s ), 8.87 (1H, d, J= 10 Hz)

Reference Example 14

Synthesis of (+)-methyl(S)-[N-[1-(t-butoxycarbony)-2-methylpropyl]]aminocrotonate:

0.018 g (0.3 mol) of acetic acid was added to a mixture of 3.484 g (30mmol) of methyl acetoacetate and 5.458 g (31.5 mmol) of L-valine t-butylester. The mixture was then stirred for 24 hours and dissolved in 45 mlof benzene. The reaction mixture was washed and dried over anhydroussodium sulfate. The solvent was distilled away from the reaction mixtureunder reduced pressure, whereby 8.14 g (100%) of the captioned compoundwas obtained. Optical rotation [α]_(D) ²⁵ =+131° [c=1.02, ethanol]NMR(δ, CDCl₃) 1.01 (6H, d, J=7 Hz), 1.47 (9H, s), 1.86 (3H, s), 2.09-2.23(1H, m), 3.64 (3H, s), 3.78 (1H, dd, J=10 Hz, 6 Hz), 4.52 (1H, s), 8.87(1H, d, J=10 Hz)

EXAMPLE 96

Synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]amino]acetate:##STR139##

More specifically, a tetrahydrofuran solution containingphenylmagnesiumbromide in an amount of 1.2 equivalents was prepared bydissolving 0.153 g (6.3 g atom) of magnesium, 0.075 g (0.4 mmol) of1,2-dibromoethane and 0.832 g (5.3 mol) of bromobenzene in 20 ml ofanhydrous tetrahydrofuran. In an atmosphere of argon gas, atetrahydrofuran solution containing the phenylmagnesiumbromide was addeddropwise to 12 ml of an anhydrous tetrahydrofuran solution containing1.194 g (4.4 mmol) of (-)-methyl(R)-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate at -15° C.and the mixture was further stirred for one hour. The reaction mixturewas cooled to -70° C. and an anhydrous tetrahydrofuran solutioncontaining 1.359 g (3.9 mmol) of t-butyl2-[N-[2-(3-nitrobenzylidene)-3-oxobutanoyl]amino]acetate was addeddropwise thereto. After the completion of the dropwise addition of thetetrahydrofuran solution, the reaction mixture was further stirred for 3hours. To the obtained reaction mixture, 11 ml of 1N hydrochloric acidwas added dropwise and the temperature of the reaction mixture wasraised to room temperature. An organic layer was separated from thereaction mixture. A water layer was extracted with tetrahydrofuran. Theextracted layer by the tetrahydrofuran was combined with the organiclayer, washed with a saturated aqueous solution of sodium chloride anddried over anhydrous sodium sulfate. The solvent was distilled away fromthe mixture under reduced pressure. The residue was dissolved in 20 mlof methanol and 3.39 g (44 mmol) of ammonium acetate was added thereto.The mixture was then stirred at room temperature overnight. The solventwas distilled away from the mixture under reduced pressure. The residuewas dissolved in methylene chloride, washed with a saturated aqueoussolution of sodium hydrogencarbonate, and dried over anhydrous sodiumsulfate. The solvent was distilled away from the mixture under reducedpressure. The residue was chromatographed on a silica gel column forpurification, whereby 1.39 g (80%) of the captioned compound with anoptical rotation of [α]_(D) ²⁵ =+14.6° (c=0.5327, ethanol) was obtained.Furthermore, the captioned compound with the following physicalproperties was obtained by recrystallization.

Melting point (°C.) 140.9-142.4 IR (υcm⁻¹, KBr) 3328, 1742, 1682, 1532,1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd. 445.18484Found 445.18726 NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s), 2.34 (3H, s),3.66 (3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62 (1H, s), 5.86(1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵ =+18.3°[c=1.0264, ethanol]

EXAMPLE 97

Synthesis of (-)-t-butyl(R)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3-yl]carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR140##

The procedure for the synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]amino]acetatein Example 96 was repeated except that the (-)-methyl(R)-[N-[1(t-butoxycarbonyl)- 2-methylpropyl]]aminocrotonate employed inExample 96 was replaced by 1.194 g (4.4 mmol) of (+)-methyl(S)-[N-[1-t-butoxycarbonyl)-2-methylpropyl]]aminocrotonate, whereby 1.39g (80%) of the captioned compound with an optical rotation of [α]_(D) ²⁵=+15.2° [c=0.5001, ethanol]was obtained. Furthermore, the captionedcompound with the following physical properties was obtained byrecrystallization.

Melting point (°C.) 140.0-141.8 IR (υcm⁻¹, KBr) 3328, 1742, 1682, 1532,1352 Mass spectrometry C₂₂ H₂₇ N₃ O₇ Calcd. 445.18484 Found 445.18655NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s), 2.34 (3H, s), 3.66 (3H, s),3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62 (1H, s), 5.86 (1H, t, J=5 Hz),7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04 (1H, d, J=8 Hz),8.13 (1H, S) Optical rotation [α]_(D) ²⁵ =-18.4° [c=1.053, ethanol]

Reference Example 15

Synthesis of (+)-t-butyl(S)-2-[N-[3-[N-[1-(t-butoxycarbonyl)-2-methylpropyl]amino]-2-butenoyl]amino]-acetate:

A mixture of 4.305 g (20 mmol) of t-butyl2-[N-(3-oxobutanoyl)amino]acetate and 3,811 g (22 mmol) of L-valinet-butyl ester was stirred at room temperature for 15 hours. The reactionmixture was dissolved in benzene and dried over anhydrous sodiumsulfate. The solvent was distilled away from the reaction mixture underreduced pressure, whereby 7.41 g (100%) of the captioned compound wasobtained. Optical rotation [α]_(D) ²⁵ =+114.5° [c=0.9415, ethanol]NMR(δ, CDCl₃) 1.00 (6H, d, J=7 Hz), 1.46 (18H, s), 1.81 (3H, s), 2.08-2.22(1H, m), 3.71 (1H, dd, J=10 Hz, 6 Hz), 3.95 (2H, d, J=5 Hz), 4.41 (1H,s), 5.29 (1H, t, J=5 Hz), 9.33 (1H, d, J=10 Hz)

Reference Example 16

Synthesis of (-)-t-butyl(R)-2-[N-[3-[N-[1-(t-butoxy-carbonyl)-2-methylpropyl]amino]-2-butenoyl]amino]-acetate:

A mixture of 4.305 g (20 mmol) of t-butyl2-[N-(3-oxobutanoyl)aminocrotonate acetate and 3.811 g (22 mmol) ofD-valine t-butyl ester was stirred at room temperature for 15 hours. Thereaction mixture was dissolved in benzene and dried over anhydroussodium sulfate. The solvent was distilled away under reduced pressure,whereby 7.41 g (100%) of the captioned compound was obtained. Opticalrotation [α]_(D) ²⁵ =-114.5° [c=0.8447, ethanol]NMR (δ, CDCl₃) 1.00 (6H,d, J=7 Hz), 1.46 (18H, s), 1.81 (3H, s), 2.08-2.22 (1H, m), 3.71 (1H,dd, J=10 Hz, 6 Hz), 3.95 (2H, d, J=5 Hz), 4.41 (1H, s), 5.29 (1H, t, J=5Hz), 9.33 (1H, d, J=10 Hz)

EXAMPLE 98

Synthesis of (+)-t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3yl]-carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR141##

More specifically, a tetrahydrofuran solution containingphenylmagnesiumbromide in an amount of 1.2 equivalents was prepared bydissolving 0.656 g (27 mg atom)of magnesium, 0.188 g (1 mmol) of1,2-dibromoethane and 3.768 g (24 mmol) of bromobenzene in 24 ml ofanhydrous tetrahydrofuran. In an atmosphere of argon gas, thetetrahydrofuran solution containing the phenylmagnesiumbromide was addeddropwise to 74 ml of an anhydrous tetrahydrofuran solution containing7.41 g (20 mmol) of (+)-t-butyl(S)-2-[N-[3-[N-[(1-t-butoxycarbonyl)-2-methylpropyl]amino]-2-butenoyl]amino]acetateat -15° C. and the reaction mixture was stirred for one hour. Thereaction mixture was cooled to -50° C. and an anhydrous tetrahydrofuransolution containing 4.735 g (19 mmol) of methyl 2-(3-nitrobenzylidene)acetoacetate was added dropwise thereto. After the completion of thedropwise addition of the tetrahydrofuran solution, the reaction mixturewas further stirred for 3 hours. To the obtained reaction mixture, 47 mlof 1N hydrochloric acid was added dropwise and the temperature of thereaction mixture was raised to room temperature. An organic layer wasseparated from the reaction mixture. A water layer was extracted withtetrahydrofuran. The layer extracted with tetrahydrofuran was combinedwith the organic layer, washed with a saturated aqueous solution ofsodium chloride and dried over anhydrous sodium sulfate. The solvent wasdistilled away from the mixture under reduced pressure. The residue wasdissolved in 89 ml of methanol. With the addition of 15.4 g (200 mmol)of ammonium acetate, the residue was stirred at room temperatureovernight. The solvent was distilled away from the mixture under reducedpressure. The residue was chromatographed on a silica gel column forpurification, whereby 6.764 g (80%) of the captioned compound with anoptical rotation of [α]_(D) ²⁵ =+16.1° (c=0.499, ethanol) was obtained.Furthermore, the captioned compound with the following physicalproperties was obtained by recrystallization.

Melting point (°C.) 140.9-142.4 IR (υcm⁻¹, KBr) 3328, 1742, 1682, 1532,1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃)₇ Calcd. 445.18484Found 445.18726 NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s), 2.34 (3H, s),3.66 (3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62 (1H, s), 5.86(1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵ =+18.3°[c=1.0264, ethanol]

EXAMPLE 99

Synthesis of (-)-t-butyl (R)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR142##

The procedure for the synthesis of (+)-t-butyl(s)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-yl]carbonyl]amino]acetatein Example 98 was repeated except that (+)-t-butyl(S)-2-[N-[3-[N-[(1-t-butoxycarbonyl)-2-methylpropyl]amino]-2butenoyl]amino]acetateemployed in Example 98 was replaced by 7.41 g (20 mmol) of (-)-t-butyl(R)-2-[N-[3-[N-[(1-t-butoxycarbonyl)-2-methylpropyl]amino]-2-butenoyl]-amino]acetate,whereby, 6.764 g (80%) of the captioned compound with an opticalrotation of [α]_(D) ²⁵ =-15.8° (c=0.499, ethanol) was obtained.Successively, the captioned compound with the following physicalproperties was obtained by recrystallization.

Melting point (°C.) 140.0-141.8 IR (υcm⁻¹, KBr) 3328 , 1742, 1682, 1532,1352 Mass spectrometry Based on Formula C₂₂ H₂₇ N₃ O₇ Calcd. 445.18484Found 445.18655 NMR (δ, CDCl₃) 1.44 (9H, s), 2.31 (3H, s), 2.34 (3H, s),3.66 (3H, s), 3.88 (2H, d, J=5 Hz), 4.96 (1H, s), 5.62 (1H, s), 5.86(1H, t, J=5 Hz), 7.42 (1H, dd, J=8 Hz, 8 Hz), 7.69 (1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz), 8.13 (1H, s) Optical rotation [α]_(D) ²⁵ 18.4°[c=1.053, ethanol]

EXAMPLE 100

Synthesis of t-butyl2-[N-(5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3-carbonyl)amino]acetate:

The above compound was synthesized in accordance with the followingreaction scheme: ##STR143##

A toluene solution containing 348 mg (1 mmol) of t-butyl2-[N-[3-oxo-2-(3-nitrobenzylidene)butanoyl]amino]acetate and 123 mg (1.5mmol) of 3-aminocrotonitrile was refluxed for 4 hours. The reactionmixture was chromatographed on a silica gel column for purification,whereby 407 mg (98.7%) of t-butyl2-[N-(5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-nitro-phenyl)pyridine-3-carbonyl)amino]acetatewas obtained.

Melting point (°C.) 181.8-183.1 IR (υcm⁻¹, KBr) 3308, 2196, 1706, 1676,1526, 1352 Mass spectrometry Based on Formula C₂₁ H₂₄ N₄ O₅ Calcd.412.17464 Found 412.17500 NMR (δ, CDCl₃) 1.42 (9H, s), 2.12 (3H, s),2.28 (3H, s), 3.78 (1H, dd, J=18 Hz, 6 Hz), 3.87 (1H, dd, J=18 Hz, 6Hz), 4.69 (1H, s), 5.76 (1H, t, J=6 Hz), 5.81 (1H, s), 7.52 (1H, dd,J=8H, 8 Hz), 7.68 (1H, d, J=8 Hz), 8.12 (1H, s), 8.14 (1H, d, J=8 Hz)

1. Test for hypotensive activity

The test was carried out by employing spontaneously hypertensive rats(aparalytice SHR; male) according to Nakao et al method.

The blood pressures in the whole body of the rats were measured with apressure transducer (MPU-0.5, made by Nihon Koden K.K.) through a canulainserted into the abdominal aorta through the aorta of its tail.Successively, 100 μg/kg of each compound to be tested was administratedinto the vein of its tail of SHR through a canula (previously inserted),whereby the hypotensive activity of each compound was examined. Theresults are shown in Table 10.

                  TABLE 10                                                        ______________________________________                                        Compound of Example                                                                           Hypotensive Activity (mmHg)                                   ______________________________________                                        1       (Compound a)                                                                              90                                                        1       (Compound b)                                                                              105                                                       2       (Compound a)                                                                              35                                                        2       (Compound b)                                                                              35                                                        3                   40                                                        4                   105                                                       7                   80                                                        8                   25                                                        9                   100                                                       12                  75                                                        13      (Compound b)                                                                              90                                                        15                  90                                                        22      (Compound a)                                                                              90                                                        23                  70                                                        32                  60                                                        34                  30                                                        35                  50                                                        36                  35                                                        37                  30                                                        38                  20                                                        48                  92.5                                                      49                  105                                                       50      (Compound a)                                                                              107.5                                                     66                  30                                                        90                  70                                                        ______________________________________                                    

2. Test for platelet aggregation-inhibiting activity of rabbit.

A blood of a rabbit (Japanese white; male; 2.5-3.0 kg) was exsanguinatefrom a carotid of the rabbit, and nine parts of the blood were mixedwith one part of a 3.8% aqueous solution of sodium citrate. The mixturewas centrifuged at 1100 rpm at 20° C. for 15 minutes, so that a plateletpoor plasma (PPP) was obtained.

10 μl of a solution of the compound to be tested was added to 200 μl ofPRP, and the mixture was subjected to incubation at 37° C. for 10minutes. To the mixture was added 10 μl of a platelet activating factor(PAF) (10 mg/ml). The agglutination was measured by Agricometer (NKK,PAT-4A). The Platelet aggregation-inhibiting concentration to eachaggregation agent of each compound is shown in Table 11.

                  TABLE 11                                                        ______________________________________                                                        Platelet Aggregation-                                         Compound of Example                                                                           Inhibiting Activity (%)                                       ______________________________________                                        1       (Compound a)                                                                              42.8                                                      2       (Compound a)                                                                              25.5                                                      2       (Compound b)                                                                              98.2                                                      3                   100                                                       7       (Compound a)                                                                              54.1                                                      8                   39.1                                                      9                   29.8                                                      13      (Compound a)                                                                              37.7                                                      18      (Compound a)                                                                              33.8                                                      19      (Compound a)                                                                              35.4                                                      22      (Compound a)                                                                              20.2                                                      23                  33.6                                                      24      (Compound a)                                                                              24.3                                                      27      (Compound a)                                                                              33.3                                                      32                  100                                                       33                  94.2                                                      34                  100                                                       35                  32.3                                                      36                  100                                                       37                  100                                                       38                  100                                                       47                  32.7                                                      48                  41.5                                                      49                  38.9                                                      50      (Compound a)                                                                              23.5                                                      52      (Compound a)                                                                              29.2                                                      57                  64.5                                                      58                  22.1                                                      60                  47.2                                                      62                  64.3                                                      63                  100                                                       64                  52.6                                                      65                  42.7                                                      66                  100                                                       67                  33.8                                                      68                  34.1                                                      69                  23.3                                                      70                  27.1                                                      71                  100                                                       76                  46.3                                                      79                  100                                                       ______________________________________                                    

The 1,4-dihydropyridine derivatives and optical active1,4-dihydropyridine derivatives according to the present invention havevasodilating activity based on calcium antagonism, and PAF antagonism,so that these 1,4-dihydropyridine derivatives are useful as remedies fordiseases of circulatory system, such as hypotensor, cerebral circulationimprovement agent, and antithrombotic agent, and remedies for allergicdiseases, such as antiasthmatic, anti-inflammatory agent, andantiallergic agent. Furthermore, the present invention provides simpleand efficient methods of producing the optical active1,4-dihydropyridine derivatives.

What is claimed is:
 1. 1,4-dihydropyridine compounds of formula (I):##STR144## wherein R²¹ is selected from the group consisting of NO₂, Cl,and CN, R²² is selected from the group consisting of hydrogen and methylgroup, R²³ is selected from the group consisting of hydrogen and C_(n)H_(2n+1), wherein n is an integer of from 1 to 4, and R²⁴ is selectedfrom the group consisting of C_(n) H_(2n+1) and alkoxyl-substitutedC_(n) H_(2n+1), wherein n is an integer of from 1 to 4, wherein theconfiguration of the 1,4-dihydropyridine ring is specified as S.
 2. The1,4-dihydropyridine compound as in claim 1, wherein formula (I) ist-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]amino]acetate.3. The 1,4-dihydropyridine compound as in claim 1, where formula (I) ist-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-cyanophenyl)pyridine-3-carbonyl]amino]acetate.4. The 1,4 -dihydropyridine compound as in claim 1, wherein formula (I)is t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate.5. The 1,4 -dihydropyridine compound as in claim 1, wherein formula (I)is t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate.6. The 1,4 -dihydropyridine compound as in claim 1, wherein formula (I)is t-butyl2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl)-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate.7. The 1,4 -dihydropyridine compound as in claim 1, wherein formula (I)is t-butyl(S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3yl]carbonyl]amino]acetate.